The Targeted Pulse: FDA Decisions and Trial Updates

Welcome to the final edition of The Targeted Pulse of 2025, your weekly wrap-up of the top developments in oncology. This week, we saw groundbreaking FDA decisions across multiple cancer types establishing new standards of care for patients.

FDA Approves T-DXd Plus Pertuzumab for HER2-Positive Breast Cancer

On December 15, 2025, the FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) for the first-line treatment of unresectable or metastatic HER2-positive breast cancer. This decision, based on the phase 3 DESTINY-Breast09 trial, establishes a new standard-of-care.

The combination demonstrated a median progression-free survival (PFS) of 40.7 months compared to 26.9 months with standard taxane, trastuzumab, and pertuzumab (HR, 0.56; P < 0.0001). The objective response rate (ORR) was 87% vs 81%, respectively. Clinicians should monitor for established class-specific toxicities, including neutropenia, left ventricular dysfunction, and interstitial lung disease. Dosing involves T-DXd 5.4 mg/kg with pertuzumab every 3 weeks.

Enfortumab Vedotin Plus Pembrolizumab Improves Survival in MIBC

The phase 3 EV-304/KEYNOTE-B15 trial demonstrated that perioperative enfortumab vedotin (Padcev) combined with pembrolizumab (Keytruda) significantly improves event-free survival and overall survival (OS) compared to neoadjuvant gemcitabine/cisplatin in cisplatin-eligible patients with muscle-invasive bladder cancer. This marks the first non-platinum regimen to surpass standard chemotherapy in this setting.

Additionally, the combination achieved superior pathologic complete response rates. The safety profile remained consistent with established data for both agents, with no new signals. These findings, alongside the EV-303 data for cisplatin-ineligible patients, support enfortumab vedotin plus pembrolizumab as a potential new perioperative standard-of-care regardless of cisplatin eligibility.

Long-Term ECHO Data Support Concurrent Acalabrutinib/BR in MCL

The phase 3 ECHO trial demonstrates that adding acalabrutinib (Calquence) to bendamustine and rituximab (Rituxan; BR) significantly improves outcomes in older, transplant-ineligible patients with previously untreated mantle cell lymphoma (MCL). At 45 months of follow-up, the acalabrutinib-BR arm achieved a median PFS of 66.4 months compared to 49.6 months with BR alone (HR, 0.73, P = 0.016). Complete response rates also favored the triplet (66.6% vs 53.5%).

Notably, after censoring for COVID-19 deaths, the PFS hazard ratio improved to 0.64, with a favorable overall survival trend (HR, 0.75). The safety profile was manageable; although infections were higher (41.1% vs 34.0%), incidence rates of atrial fibrillation and major bleeding remained low. These data establish acalabrutinib-BR as a new frontline standard-of-care for older patients with MCL.

Teclistamab/Daratumumab Earns FDA Priority Voucher for R/R Myeloma

The FDA has awarded a national priority voucher to the combination of teclistamab-cqyv (Tecvayli) plus daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro; Tec-Dara) for patients with relapsed/refractory (R/R) multiple myeloma. This designation, based on the phase 3 MajesTEC-3 trial, aims to expedite the approval of this steroid-sparing, BCMA/CD38-targeted regimen as a new standard-of-care for patients with 1–3 prior lines of therapy.

In the trial, Tec-Dara demonstrated an 83% reduction in the risk of progression or death compared to standard daratumumab-based triplets (HR, 0.17; P<0.0001). At 36 months, the PFS rate was 83.4% vs 29.7% for the control. Additionally, OS significantly favored the combination (HR, 0.46; P<0.0001), with an 83.3% 3-year OS rate. Safety was consistent with known profiles; while infections were more frequent initially, they declined over time with prophylactic management. This regimen offers a potent, potentially steroid-free option for early relapse.

FDA Fast-Tracks Muzastotug Combo in MSS Metastatic Colorectal Cancer

The FDA has granted fast track designation to the combination of muzastotug (ADG126) and pembrolizumab for adult patients with microsatellite stable metastatic colorectal cancer without active liver metastases. Muzastotug is a next-generation SAFEbody anti-CTLA-4 antibody engineered with a masked domain that selectively activates in the tumor microenvironment. This design aims to enhance regulatory T-cell depletion while minimizing the systemic immune-related toxicities typical of first-generation CTLA-4 inhibitors.

In a phase 1b/2 study, the combination demonstrated promising activity in heavily pretreated patients, with ORRs up to 29% and a manageable safety profile (no grade 4/5 treatment-related adverse events). A registrational phase 3 trial is planned for 2027.