Category: 3. Business

Sirexatamab (DKN-01) in combination with bevacizumab (Avastin) and standard-of-care (SOC) chemotherapy demonstrated a manageable safety profile and was well tolerated vs bevacizumab plus SOC chemotherapy in patients with metastatic colorectal cancer (mCRC), according to findings from the phase 2 DeFianCe trial (NCT05480306) presented at the 2025 ESMO Congress. Notably, patients with DKK1-high tumors derived improvements in both progression-free survival (PFS) and overall survival (OS).

In the intent-to-treat population, patients who received the DKK1 inhibiting IgG4 antibody sirexatamab demonstrated an overall response rate (ORR) of 35.1% (95% CI, 25.5%-45.6%) vs 26.6% (95% CI, 18.0%-36.7%) for the control arm (P = .10). Median PFS was 9.2 months in the experimental arm vs 8.3 months in the control arm (P = .17).

“Neither of these 2 outcomes reached statistical significance,” lead author Zev A. Wainberg, MD, said during the presentation of data. “However, looking at the DKK1-high population, defined as the upper median, the improvement started to bear fruit,” Wainberg, professor of medicine at UCLA and codirector, UCLA GI program, at UCLA Health in California continued.

There were 50 patients with higher DKK1 in the sirexatamab arm and 38 in the control arm. The ORR in the sirexatamab arm was 38.0% (95% CI, 24.7%-52.8%) vs 23.7% (95% CI, 11.4%-40.2%) in the control arm (P = .0706). Median PFS in the experimental arm was 9.03 months vs 7.06 months (HR, 0.61; 95% CI, 0.37-1.0; P = .0255). Median OS was not reached in the experimental arm vs 14.39 months in the control arm (HR, 0.42; 95% CI, 0.19-0.91; P = .0118).

What Was the DeFianCe Trial Design?

After an initial safety run-in period (n = 33), a total of 188 patients with mCRC were randomly assigned 1:1 to receive either sirexatamab plus either leucovorin, 5-fluorouracil (5-FU), and irinotecan (FOLFIRI) or leucovorin, 5-FU, and oxaliplatin (FOLFOX) and bevacizumab (n = 94) vs FOLFIRI or FOLFOX and bevacizumab (n = 94).

Patients were eligible if they had received 1 prior 5-FU–based therapy, had microsatellite stable (MSS) CRC, and did not have a BRAF V600 mutation. The stratification factors were tumor sidedness (left vs right) and prior antiangiogenesis therapy (yes vs no).

The primary end point was investigator-assessed PFS and the secondary end points were safety, ORR, and OS. Key exploratory end points were PFS, ORR, and the OS of the DKK1-high subgroup.

What Were the Patient Baseline Characteristics?

The study was well-balanced for gender and region. The majority of patients were male across the arms (experimental, 68%; control, 55%). In the experimental arm, the majority of patients were from South Korea (53%) compared with 48% in the control arm. Forty-four percent of patients were from the United States in the experimental arm and 43% in the control arm. The majority of patients had left-sided tumors (both 75%).

“This was a predominantly liver-metastatic patient population, with nearly 75% in both arms having liver metastatic disease,” Wainberg said. Further, 47% of patients in the experimental arm had RAS-mutated disease compared with 57% in the control arm. Looking at prior systemic therapy, 48% of patients in the experimental arm had received antiangiogenesis therapy compared with 51% in the control arm.

What Was the Safety Profile?

The overall rate of treatment-emergent adverse events (TEAEs) for sirexatamab was similar to the chemotherapy arm, suggesting that the addition of the agent does not adversely impact the safety profile of the combined agents.

In the experimental arm, 15% of patients discontinued therapy compared with 19% in the control arm. In the patients with DKK1-high status, 4% discontinued in the treatment arm vs not applicable in the control arm. Dose reductions affected 37% of patients in the experimental arm compared with 43% in the control arm. Dose interruptions were similar, with 73% in the experimental arm and 71% in the control arm.

“These data support continued development of sirexatamab in DKK1-high previously treated patients with mCRC,” Wainberg concluded.

Disclosures: Dr Wainberg disclosed that he has provided consulting services to Alligator Therapeutics, Amgen, AstraZeneca, Arcus, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo Company, Eli Lilly and Company, EMD Serono, Roche AG, Genentech, Ipsen, Johnson & Johnson, Merus NV, Merck, Novartis, Novocure, Pfizer, Servier, and Verastem.

Reference

Wainberg ZA, Han S-W, Kim JG, et al. DeFianCe Trial: A randomized phase 2 trial of sirexatamab (DKN-01) plus bevacizumab and chemotherapy versus bevacizumab and chemotherapy as second-line therapy in advanced microsatellite stable (MSS) colorectal cancer (CRC). Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA34.

The novel HER2-targeted antibody-drug conjugate (ADC) trastuzumab rezetecan (SHR-A1811) reduced the risk of disease progression or death by 78% compared with the standard combination of pyrotinib (Irene) plus capecitabine in patients with previously treated HER2-positive advanced breast cancer, according to findings from the phase 3 HORIZON-Breast01 trial (NCT05424835) presented at the 2025 ESMO Annual Congress.¹

At an overall median follow-up of about 15.5 months, the median progression-free survival (PFS) by blinded independent central review (BICR) was 30.6 months (95% CI, 16.8–not reached) in the trastuzumab rezetecan arm compared with 8.3 months (95% CI, 6.9–11.0) in the combination arm (HR, 0.22; 95% CI, 0.15–0.34; P <.0001). The 12-month PFS rates were 84.7% vs 35.5%, respectively.

The median investigator-assessed PFS was 33.3 months vs 8.1 months, respectively (HR, 0.16; 95% CI, 0.10–0.25). Per the investigators, the 12-month PFS rate was 86.7% vs 36.0% in the experimental vs combination arms, respectively.

The median PFS benefit with trastuzumab rezetecan was upheld across all predefined patient subgroups. Of note, the benefit was sustained regardless of prior pertuzumab (Perjeta) treatment and regardless of the number of prior lines of therapy.

The overall survival (OS) data remained immature at the time of the data cutoff; however, there was a trend toward an OS benefit with trastuzumab rezetecan. The 12-month OS rate was 96.3% with the ADC vs 88.4% with the combination (HR, 0.31; 95% CI, 0.14–0.69).

“Notably, 50.3% of patients in the combination arm received an anti-HER2 ADC as post-study anticancer treatment, suggesting the initial trend we observed with the OS benefit [for trastuzumab rezetecan] might be meaningful,” said presenting author Erwei Song, MD, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

The objective response rate (ORR) was 81.7% vs 55.9% in the ADC vs combination arms, respectively. The complete response, partial response, and stable disease rates were 4.2% vs 2.8%, 77.5% vs 53.15%, and 14.1% vs 31.0%, respectively. The disease control rate was 95% vs 86.9% and the progressive disease rate was 0.7% vs 9%, respectively. The median duration of response was 27.8 months vs 10.9 months, respectively.

The median treatment duration was 19.5 months for the ADC, 7.1 months for pyrotinib, and 7.5 months for capecitabine, indicating the ADC was well tolerated. Regarding safety, 13.4% of the ADC arm experienced serious treatment-emergent adverse events (TEAEs) vs 11.8% of the combination arm. The rate of discontinuations due to TEAEs was 4.9% vs 1.4%, respectively.

Song also noted that the majority of patients in the ADC arm had hematologic toxicities, with about 89.4% of patients experiencing neutrophil count decrease across all grades compared with 45.1% in the combination arm. He also noted that only 2.8% of the ADC arm experienced interstitial lung disease (ILD), including only 1 patient with grade 3 ILD.

“Trastuzumab rezetecan exhibited a significant PFS benefit and a strong trend in OS vs pyrotinib plus capecitabine in patients with HER2-positive advanced/metastatic breast cancer previously treated with trastuzumab and a taxane,” Song said.

What Was the Study Design of the HORIZON-Breast01 Trial?

The open-label, multicenter phase 3 HORIZON-Breast01 study enrolled 287 patients with HER2-positive unresectable or metastatic breast cancer who had prior treatment with a taxane and trastuzumab (Herceptin) in the advanced setting.

Patients were randomized to trastuzumab rezetecan (n = 142; 4.8 mg/kg IV on day 1 of 21-day cycles) or the combination of pyrotinib (n = 145; 400 mg once daily oral on days 1–21 of 21-day cycles) and capecitabine (1000 mg/m² orally twice daily on days 1–14 of 21-day cycles). Treatment was administered until disease progression, patient withdrawal, unacceptable toxicity, or investigator decision.

The primary outcome measure was PFS per BICR. Secondary end points included PFS per investigator assessment, OS, ORR, duration of response, and safety.

What Were the Patient Characteristics in the HORIZON-Breast01 Trial?

The study enrolled 287 eligible patients with HER2-positive breast cancer between August 4, 2022, and August 9, 2024. The data cutoff date was June 30, 2025.

Across the overall study population, the median age was 56 years (range, 27–74), about three-fourths of patients had IHC 3+ HER2 status and the remainder had IHC 2+ and ISH+ status. Almost half of patients were hormone receptor-positive. About three-fourths of patients in the trial had visceral metastases and about 47% had more than 3 organs with tumor metastases. The ECOG performance status (PS) was evenly split between 0 and 1 in the trastuzumab rezetecan arm, while in the combination arm, 58% were ECOG PS 0 and 42% were ECOG PS 1.

The median number of prior treatment lines across all patients was 1 (range, 1–4). Most patients had received 1 prior line of therapy at 83.8% and 76.6% in the trastuzumab rezetecan and combination arms, respectively. In the experimental arm, 39.4% of patients had primary resistance to trastuzumab compared with 44.8% of patients in the combination arm. All patients had prior taxane therapy and all except 3 patients had prior trastuzumab. Three-fourths of patients overall had prior pertuzumab. Prior trastuzumab emtansine and endocrine therapy had been received by 4.9% vs 6.9% and 29.6% vs 28.3% of the 2 arms respectively.

In his concluding remarks, Song said “Trastuzumab rezetecan represents a promising practice-changing therapeutic alternative in this patient population.”

REFERENCE:

Song E, Yao H, Li H, et a. LBA19 – SHR-A1811 versus pyrotinib plus capecitabine in human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (BC): A multicenter, open-label, randomized, phase III study (HORIZON-Breast01). Results of a phase II study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA19.

The addition of tislelizumab-jsgr (Tevimbra) to induction chemotherapy and concurrent chemoradiotherapy (CRT) boasted higher composite complete response (cCR) rates, which translated to improved survival vs the historical control of concurrent CRT alone, in patients with esophageal squamous cell carcinoma (ESCC), according to data from the phase 2 EC-CRT-002 trial (NCT05520619) presented at the 2025 ESMO Congress.¹

Patients were randomly assigned to group A (n = 57) or group B (n = 57). Investigators also included a historical control group for comparison consisting of 55 patients from a phase 2 trial (NCT02403531) who experienced a 1-year PFS rate of 56% with concurrent CRT alone. Patients in group A received induction chemotherapy consisting of paclitaxel plus cisplatin every 3 weeks for 2 cycles; concurrent CRT with intensity modulated radiation therapy at 50.4 Gy over 28 fractions and paclitaxel plus cisplatin every week for 5 cycles; and tislelizumab at 200 mg every 3 weeks for a total of 16 cycles (induction, n = 2; concurrent, n = 2; adjuvant, n = 12). Patients in group B received the same treatment schedule with the exception that tislelizumab was only administered for a total of 4 cycles (induction, n = 2; concurrent, n = 2).

The 1-year progression-free survival (PFS) rate in group A was 52% vs 56% with the control (P = .52). The 1-year PFS rate in group B was 73% vs 56% with the control (P = .024). The 1-year overall survival (OS) rates were 82% and 69% in group A and the control arm, respectively (P = .32). The respective 1-year OS rates in group B vs the control arm were 85% and 69% (P = .004).

“Tislelizumab plus induction chemotherapy and concurrent CRT demonstrated superior efficacy and manageable toxicity compared [with] chemoradiotherapy alone in locally advanced ESCC,” Mian Xi, MD, lead study author and chief physician of radiation oncology at Sun Yat-Sen University Cancer Center in Guangzhou, China, said in a presentation.

What Is the Background of the EC-CRT-002 Trial?

Definitive CRT is the preferred standard of care (SOC) for patients with locally advanced ESCC. Findings from a prior randomized phase 2 trial (NCT02403531) led by Xi failed to show an OS benefit with the addition of induction chemotherapy to definitive CRT vs definitive CRT alone in patients with ESCC.² However, patients who responded to induction chemotherapy displayed improved OS vs those in the CRT alone arm.

As such, investigators theorized that combining anti–PD-1 therapy with induction chemotherapy and concurrent CRT could improve OS, resulting in a new SOC for patients with locally advanced disease.

This served as the basis for the present multicenter, randomized, parallel-group, phase 2 trial. To be eligible for enrollment, patients had to have newly diagnosed, unresectable, locally advanced, histologically confirmed ESCC; be between the ages of 18 and 70 years; have an ECOG performance status of 0 to 2; and have no history of a concomitant or prior malignancy.

The primary end point was PFS. Secondary end points were OS, cCR, safety, and quality of life.

Between October 2022 and October 2024, 114 patients were randomly assigned to receive treatment. The data cutoff was July 31, 2025.

What Did the Demographic Information Reveal About the Patients in the EC-CRT-002 Trial?

Baseline characteristics in group A (n = 57) indicated that most patients were male (84%) and had upper (49%) or middle (37%) as opposed to distal (14%) tumors. The median age was 61 years (range, 38-70), and represented cTNM stages were II (5%), III (33%), IVA (39%), and IVB (23%). In group B (n = 57), most patients were male (75%) and had upper (42%) or middle (42%) vs distal (16%) tumors. The median age was 61 years (range, 37-70), and cTNM stages included II (4%), III (32%), IVA (39%), and IVB (26%).

What Other Efficacy Data Were Presented From the EC-CRT-002 Trial, and What Was the Safety Profile of the Regimen?

The cCR rates were 51% and 40% in group A vs the control arm (P = .334). Patients in group B and the control arm experienced cCR rates of 70% and 40%, respectively (P = .003).

Treatment-related adverse effects included lymphopenia (74.6%), esophagitis (16.7%), anemia (14.9%), leukopenia (13.2%), neutropenia (8.8%), pneumonitis (2.6%), esophageal fistula (2.6%), alanine aminotransferase/aspartate aminotransferase level elevation (1.8%), and rash (0.9%).

Exploratory analysis revealed that patients with PD-L1 combined positive scores (CPS) of 1 or greater had improved PFS vs those with PD-L1 CPS below 1 (P = .036). Moreover, patients with higher levels of CD8 positivity had improved PFS (P = .017). Patients who tested negative for circulating tumor DNA also experienced improved survival (P < .001).

“[The] benefit of adjuvant immunotherapy after definitive CRT remains uncertain,” Xi concluded.

Disclosures: Xi had no disclosures to declare.

References

1. Xi M, Chen B, Liu S, et al. Tislelizumab combined with induction chemotherapy and concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, phase II trial (EC-CRT-002). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA82.
2. Liu S, Luo L, Zhao L, et al. Induction chemotherapy followed by definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: a randomized phase II trial. Nat Commun. 2021;12(1):4014. doi:10.1038/s41467-021-24288-1

The intracranial objective response rate (ORR) in RANO-BM–evaluable patients (n = 16) was 31.3% (n = 5), which included 1 intracranial complete response. Notably, 2 of 5 intracranial responders also had leptomeningeal disease at baseline, and 4 of the 5 did not receive prior CNS radiotherapy. The intracranial disease control rate (DCR) was 68.8%, and the median intracranial duration of response (DOR) was 8.1 months (95% CI, 3.1-not evaluable).

The systemic ORR in RECIST 1.1–evaluable patients (n = 29) was 27.6% (n = 8) and the DCR was 58.6%. The median DOR was 7.6 months (95% CI, 2.07-9.07).

“Zipalertinib demonstrated clinically meaningful intracranial antitumor activity…in patients with NSCLC harboring EGFR exon 20 insertions or other uncommon single or compound uncommon mutations,” Helena A. Yu, MD, attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, stated in the presentation. “The intracranial response rate was similar to the systemic response rate in the reported population,” Yu added.

What Led to Zipalertinib’s Evaluation in the REZILENT2 Trial?

Poor prognosis is associated with the presence of CNS metastases in patients with EGFR-mutant NSCLC, reflecting a clinical need for more effective treatment options.

Zipalertinib is an oral, highly selective, irreversible EGFR TKI that has proven active in advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the phase 1/2 REZILIENT1 trial (NCT04036682), including in patients with CNS metastases.²

To be eligible for enrollment in the subsequent REZILIENT2 trial, patients had to be at least 18 years of age and have received a diagnosis of locally advanced or metastatic NSCLC with documented exon 20 insertions or other uncommon single or compound non–EGFR exon 20 insertion mutations. Measurable disease per RECIST 1.1/CNS per RANO-BM criteria was also required, as was an ECOG performance status of 0 or 1.

Patients with active brain metastases had to be newly diagnosed and/or have progressing brain lesions without CNS targeted therapy and/or leptomeningeal disease. There was no limit on the number of prior therapies patients could have received in the advanced or metastatic setting.

Patients received 100 mg of oral zipalertinib twice daily until progressive disease or other discontinuation criteria were met. A total of 32 patients were enrolled, 16 of whom were evaluable by RANO-BM.

The data cutoff was February 17, 2025, and the study remains ongoing.

The primary end point was ORR per RECIST 1.1 criteria. Secondary end points included intracranial ORR, intracranial DOR, intracranial DCR per RANO-BM, and safety.

What Were the Baseline Characteristics of the Study Population?

Within the RANO-BM–evaluable population (n = 16), 62.5% had not received prior CNS radiotherapy. Among all enrolled patients (n = 32), 68.8% did not receive any prior CNS radiotherapy.

In the former population, the median age was 63.0 years (range, 23-75). Most patients were female (56%), White (63%), and had an ECOG performance status of 1 (63.0%). Almost one-fifth (19%) of patients had leptomeningeal disease. Most patients also had EGFR exon 20 insertion mutations (56%) as opposed to other EGFR mutations (44%). The median number of prior lines of systemic therapy was 2 (range, 0-4); 56% had received prior EGFR TKI therapy and 6% received prior amivantamab-vmjw (Rybrevant).

Within the total population, the median age was 62.5 years (range, 23-83). Most patients were female (56%), White (50%), and had an ECOG performance status of 1 (72.0%). Almost one-fifth (19%) of patients had leptomeningeal disease. Most patients also had EGFR exon 20 insertion mutations (66%) as opposed to other EGFR mutations (41%). The median number of prior lines of systemic therapy was 2 (range, 0-4); 44% had received prior EGFR TKI therapy and 6% received prior amivantamab-vmjw (Rybrevant).

How Safe Was the Agent?

Yu also noted that the safety profile of zipalertinib at the given dose of 100 mg twice daily was consistent with that from prior data. Yu emphasized the low incidence of EGFR-related grade 3 or greater toxicity, noting that there was no grade 3 or greater diarrhea. Moreover, 2 cases of fatal interstitial lung disease occurred.

Treatment-related adverse effects (TRAEs) that occurred in at least 15% of patients included paronychia (grade 1, 6.3%; grade 2, 15.6%; grade ≥3, 3.1%), dermatitis aceniform (grade 1, 9.4%; grade 2, 9.4%; grade ≥3, 3.1%), stomatitis (grade 1, 15.6%; grade 2, 6.3%; grade ≥3, 0%), anemia (grade 1, 9.4%; grade 2, 0%; grade ≥3, 9.4%), dry skin (grade 1, 6.3%; grade 2, 9.4%; grade ≥3, 0%), and rash (grade 1, 6.3%; grade 2, 6.3%; grade ≥3, 3.1%).

Dose interruptions due to TRAEs occurred in 15.6% of patients.

“The study is ongoing and full results from cohort C of the REZILENT2 trial will be forthcoming in a future presentation,” Yu concluded.

Disclosures: Yu reported consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, AbbVie, Novocure, Takeda, Bristol Myers Squibb/Roche, Orion Clinical; research funding from AstraZeneca (Inst), Astellas Pharma (Inst), Lilly (Inst), Novartis (Inst), Pfizer (Inst), Daiichi Sankyo (Inst), Cullinan Oncology (Inst), Janssen Oncology (Inst), Erasca, Inc (Inst), Blueprint Medicines (Inst), Black Diamond Therapeutics (Inst), and Systimmune (Inst); and other relationship with Astellas Pharma.

References

1. Yu HA, Ohashi K, Ariyasu R, et al. Activity of zipalertinib against active central nervous system (CNS) metastases in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins)/other uncommon mutations. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1847MO.
2. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in patients with Epidermal Growth Factor Receptor exon 20 insertion-positive non-small cell lung cancer previously treated with platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(21):2387-2397. doi:10.1200/JCO-25-00763

Michiel van der Heijden, MD, PhD, medical oncologist at the Netherlands Cancer Institute in Amsterdam, presented the findings at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.

At last year’s ESMO Congress in Barcelona, Spain, Thomas B. Powles, MBBS, MRCP, MD, presented findings from NIAGARA. The patient population consisted of adults with cisplatin-eligible MIBC (cT2-T4aN0/1M0), urothelial cancer or urothelial cancer with divergent differentiation or histologic subtypes, evaluated and confirmed for radical cystectomy, and with creatine clearance of 40 mL/min or lower. Patient were randomly assigned 1:1 to either the durvalumab arm or the comparator arm. Patients in the durvalumab arm received neoadjuvant durvalumab, 1500 mg intravenously every 3 weeks and gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy and 8 cycles of adjuvant durvalumab. Patients in the comparator arm received 4 cycles of gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy. The 2 primary end points were event-free survival (EFS) and pathological complete response. Regarding EFS, there was a significant reduction in risk (HR=0.68, 95% CI, 0.56-0.82). Median follow-up was 42.3 months (range 0.03-61.3 months).^2,3

Data from NIAGARA supported the FDA’s approval of neoadjuvant durvalumab in combination with gemcitabine and cisplatin, followed by adjuvant durvalumab monotherapy following radical cystectomy, for adult patients with muscle invasive bladder cancer.⁴

At ESMO 2025, van der Heijden presented HRQOL outcomes from the NIAGARA study. In NIAGARA, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D-5L were assessed via electronic device at baseline and every 4 weeks until disease progression. van der Heijden explained that the EORTC QLQ-C30 measures global health scale (GHS)/QoL as well as functional and symptom subscales. GHS/QoL and Physical, Fatigue, and Pain were included in NIAGARA as prespecified priority subscales, with a 10-point change in score compared with baseline being deemed clinically meaningful.

The EQ-5D-5L visual analogue scale is constructed for patients to rate their current overall health; for NIAGARA, the investigators reported visual analogue scale change from baseline.

A total of 439 (82.4%) of patients in the durvalumab arm completed the baseline EORTC QLQ-C30 assessment vs 450 (84.9%) patients in the comparator arm. In addition, 416 (78.0%) patients in the durvalumab arm completed the baseline and at least 1 postbaseline assessment vs 410 (77.4%) of patients in the comparator arm. The compliance rate range from baseline to adjuvant week 29 was 50.9%-82.4% in the durvalumab arm vs 44.3%-84.9% in the comparator arm.

For the EQ-5D-5L, 417 (78.2%) patients completed the baseline assessment vs 430 (81.1%) patients in the comparator arm. Further, 391 (73.4%) patients in the durvalumab arm completed the baseline and at least 1 postbaseline assessment vs 380 (71.7%) patients in the comparator arm. The compliance rate range from baseline to adjuvant week 29 was 49.9%-78.2% in the durvalumab arm vs 43.2%-81.1% in the comparator arm.

For GHS/QoL, van der Heijden reported that that the difference between arms for overall mean change from baseline (CFB) was 1.6 (95% CI, –0.44 to 3.69), and with the Physical Functioning subscale, the difference between arms for overall CFB was 1.2 (95% CI, –0.80 to 3.17). For the Fatigue subscale, the difference between arms for overall CFB was –0.9 (95% CI, –3.25 to 1.52), and for the Pain subscale, the difference between arms for overall CFB was –2.1 (95% CI, –4.44 to 0.16).

The EQ-5D-5L visual analogue scale “also did not show any difference between the treatment arms,” according to van der Heijden.

“Overall, the addition of perioperative durvalumab to neoadjuvant chemotherapy significantly improved event-free survival and overall survival without adversely affecting patient-reported outcomes,” van der Heijden said in his concluding remarks.

References

1. van der Heijden M, Powles TB, Galsky MD, et al. Health-related quality of life (HRQOL) outcomes from the NIAGARA trial of perioperative durvalumab (D) plus neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC). Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract 3069MO.
2. Powles TB, van der Heijden MS, Galsky MD, et al. A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA5.
3. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. Published online September 15, 2024. Accessed October 17, 2025. https://www.nejm.org/doi/abs/10.1056/NEJMoa2408154
4. FDA approves durvalumab for muscle invasive bladder cancer. News release. US Food & Drug Administration. Published online March 28, 2025. Accessed October 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
5. IMFINZI (durvalumab) approved in the US as first and only perioperative immunotherapy for patients with muscle-invasive bladder cancer. News release. AstraZeneca. Published online March 31, 2025. Accessed October 17, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/IMFINZI-durvalumab-approved-in-the-US-as-first-and-only-perioperative-immunotherapy-for-patients-with-muscle-invasive-bladder-cancer.html

Disitamab vedotin plus toripalimab-tpzi (Loqtorzi) demonstrated a statistically significant improvement in survival compared with standard-of-care chemotherapy as a frontline treatment for patients with HER2-expressing locally advanced or metastatic urothelial carcinoma, according to results from the phase 3 RC48-C016 trial (NCT05302284) shared at the 2025 ESMO Congress.¹ Results were simultaneously published in the New England Journal of Medicine.²

With a median survival follow-up of 18.2 months and a data cutoff date of March 31, 2025, the median progression-free survival (PFS) per blinded independent review committee (BIRC) was 13.1 months (95% CI, 11.1-16.7) with the disitamab vedotin treatment compared with 6.5 months (95% CI, 5.7-7.4) with chemotherapy, representing a 64% reduction in the risk of progression or death (HR, 0.36; 95% CI, 0.28-0.46; P <.0001). The 12- and 18-month PFS rates with disitamab vedotin were 54.5% and 38.4%, respectively, vs 16.2% and 7.5% with chemotherapy.

The median overall survival (OS) was 31.5 months (95% CI, 21.7-not evaluable) in the disitamab vedotin arm compared with 16.9 months (95% CI, 14.6-21.7) in the chemotherapy arm, correlating with a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.41-0.73; P <.0001). The 12-, 18-, and 24-month OS rates in the disitamab vedotin arm were 79.5%, 64.6%, and 52.8%; in the chemotherapy arm, these rates were 62.5%, 48.1%, and 39.4%.

The PFS and OS benefits were consistent across all prespecified subgroups.

In the disitamab vedotin arm, the overall response rate (ORR) per BIRC was 76.1% (95% CI, 70.3%-81.3%), with complete responses (CRs) in 4.5% and partial responses (PRs) in 71.6% of patients; in the chemotherapy arm, the ORR was 50.2% (95% CI, 43.7%-56.7%), with CRs in 1.2% and PRs in 49.0%. The investigator-assessed ORR with disitamab vedotin was 71.6% (95% CI, 65.5%-77.2%), with CRs in 4.1% and PRs in 67.5% of patients compared with a 49.8% ORR (95% CI, 43.3%-56.3%) with chemotherapy, comprising of CRs in 3.3% and PRs in 46.5% of patients.

The median duration of response per BIRC was 14.6 months (95% CI, 11.3-18.7) with the disitamab vedotin combination compared with 5.6 months (95% CI, 5.3-5.8) with chemotherapy. In the disitamab vedotin arm, the 6-, 12-, and 18-month DOR rates were 78.9%, 58.5%, and 42.4%; in the chemotherapy arm, these rates were 37.2%, 19.0%, and 8.7%.

“The phase 3 RC48-C016 study demonstrated for the first time superiority of an anti-HER2 antibody-drug conjugate plus an anti-PD1 inhibitor in a biomarker-selected patient population with [locally advanced and metastatic urothelial cancer],” lead study author Jun Guo, of the Key Laboratory of Carcinogenesis and Translational Research in the Department of Melanoma and Sarcoma at Peking University Cancer Hospital and Institute in Beijing, China, said in the presentation. “Disitamab vedotin plus toripalimab offers a valuable new treatment option and represents a new standard of care for the [first-line] treatment of patients with HER2-expressing [locally advanced or metastatic urothelial cancer].”

The open-label RC48-CO16 trial randomly assigned 484 patients 1:1 to receive either disitamab vedotin plus toripalimab (n = 243) or gemcitabine plus cisplatin/carboplatin (n = 241). Treatment consisted of 2.0 mg/kg of intravenous disitamab vedotin and 3.0 mg/kg of toripalimab every 2 weeks, or gemcitabine at 1000 mg/m² on day 1 and day 8 and cisplatin at 70 mg/m² on day 1 or carboplatin at area under curve 4.5 on day 1 every 3 weeks. There was no maximum number of cycles set for the disitamab vedotin treatment, and the maximum number of chemotherapy cycles was 6.

Eligible patients in the trial had no prior systemic treatment for unresectable locally advanced or metastatic urothelial cancer and central lab-confirmed HER2 immunohistochemistry of 1+, 2+, or 3+; additionally, patients were eligible for cisplatin or carboplatin, had measurable disease per RECIST v1.1, and had an ECOG performance status of 0 or 1.

The primary end points were PFS per BIRC and OS. Secondary end points included PFS by investigators, ORR, DCR, DOR, safety, and quality of life.

Subsequent systemic anticancer treatment was received by 27.2% of patients on the disitamab vedotin arm and 64.7% of the chemotherapy arm; this comprised anti–HER2-containing therapy in 2.1% and 40.2%, respectively, PD-1/PD-L1 inhibitor therapy in 10.7% and 50.2%, and both in 0.8% and 31.1%.

Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 100% of patients across both arms, and treatment-related AEs (TRAEs) occurred in 98.8% of patients on the disitamab vedotin arm and 100% of those on the chemotherapy arm. Grade 3 or higher TRAEs occurred in 55.1% and 86.9% of patients, respectively; grade 3, 4, and 5 TRAEs were observed in 44.0%, 9.9%, and 1.2% of those on the experimental arm vs 41.9%, 43.7%, and 1.4% of the chemotherapy arm. TRAEs led to treatment discontinuation in 12.3% vs 10.4%, respectively.

Any-grade and grade 3 or higher immune-related AEs occurred in 46.9% and 18.9% of the disitamab vedotin arm.

Disclosures: Guo noted having advisory board/consultant roles for MSD, Roche, Pfizer, Bayer, Novartis, Simcere, RemeGen, Shanghai Junshi Bioscience, and Oriengene.

References

1. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin (DV) plus toripalimab (T) versus chemotherapy (C) in first-line (1L) locally advanced or metastatic urothelial carcinoma (la/mUC) with HER2-expression. Presented at the 2025 European Society of Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA7.
2. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. Published online October 19, 2025. doi:10.1056/NEJMoa2511648