The Targeted Pulse: FDA Decisions, Trial Advancements, and Toxicity Management

Welcome to this week’s edition of The Targeted Pulse, our top 5 stories of the week delivered right to you. This week, we saw FDA decisions in breast and colorectal cancers and advancements in pancreatic cancer and advanced clear cell renal cell carcinoma (ccRCC). From regulatory designations for promising new drugs to crucial clinical trials, here are the top stories that shaped the week.

FDA Grants Priority Review to Dato-DXd First-Line Metastatic TNBC

The FDA has granted priority review to the supplemental biologics license application for datopotamab deruxtecan (Dato-DXd) as a first-line treatment for adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who are ineligible for immunotherapy.

Based on the phase 3 TROPION-Breast02 trial, Dato-DXd significantly improved median overall survival (OS) (23.7 vs 18.7 months; HR, 0.79; P=.0291) and nearly doubled median progression-free survival (PFS) (10.8 vs 5.6 months; HR, 0.57; P <.0001) compared with investigator-choice chemotherapy. The objective response rate (ORR) was 62.5% vs 29.3%. The safety profile remains consistent with previous studies, with common adverse events (AEs) including stomatitis and nausea. This antibody-drug conjugate (ADC) represents a potential new first-line standard of care for this high-risk population.

Pelareorep Earns FDA Fast Track for Second-Line KRAS-Mutant Metastatic CRC

The FDA has granted fast track designation to pelareorep (Reolysin), an intravenously delivered oncolytic virus, in combination with bevacizumab (Avastin) and FOLFIRI (leucovorin, fluorouracil, irinotecan) for the second-line treatment of patients with KRAS-mutant, microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).

This designation is supported by findings from the phase 1 REO 022 trial, where the combination demonstrated a 33% ORR, significantly exceeding the historical 10% for standard second-line therapy. Efficacy data showed a median PFS of 16.6 months and a median OS of 27.0 months. Mechanistically, pelareorep induces viral oncolysis and stimulates antitumor immunity, specifically expanding KRAS-mutant-specific T-cell populations. A randomized controlled trial is expected to launch in March.

FDA Accepts NDA of Zanzalintinib Combo for Pretreated Metastatic CRC

The FDA has accepted the new drug application for zanzalintinib (formerly XL092), a next-generation multikinase inhibitor, in combination with atezolizumab (Tecentriq) for the treatment of adult patients with previously treated mCRC.

Supported by the phase 3 STELLAR-303 trial, the combination demonstrated a statistically significant improvement in median OS compared with regorafenib (Stivarga) (10.9 vs 9.4 months; HR, 0.80; P =.0045) in the intention-to-treat population. Notably, patients without liver metastases showed a trend toward even greater OS (15.9 vs 12.7 months). Median PFS also favored the combination (3.7 vs 2.0 months).

Zanzalintinib’s inhibition of MET, AXL, and VEGF receptors potentially enhances immunotherapy efficacy by modulating the tumor microenvironment. Common AEs included diarrhea, hypertension, and fatigue. This regimen offers a novel, chemotherapy-free option for refractory, non-MSI-high mCRC.

Dr Shubham Pant Highlights Progress and Promise in Pancreatic Cancer Treatment

In an interview with Targeted Oncology, Shubham Pant, MD, discussed the evolving pancreatic cancer landscape, shifting from traditional chemotherapy toward precision medicine. While NALIRIFOX recently demonstrated a survival benefit over gemcitabine/nab-paclitaxel (NAPOLI-3 trial), the focus has moved to targeted agents.

Dr Pant highlighted the promise of pan-RAS inhibitors, specifically daraxonrasib (RMC-6236), and KRAS G12D-targeted therapies like zoldonrasib (RMC-9805). Emerging research also targets MTAP deletions via PRMT5 inhibitors and Claudin 18.2 using ADCs. He emphasized that next-generation sequencing is now essential at diagnosis to identify these actionable alterations and enroll patients in transformative clinical trials.

Managing Toxicity and Safety of Belzutifan in ccRCC

In a virtual Case-Based Roundtable, Sumanta Pal, MD, FASCO, and colleagues discussed the toxicity profile of belzutifan (Welireg), a HIF-2α inhibitor approved for advanced ccRCC based on the LITESPARK-005 trial.

Key safety concerns include anemia and hypoxia. Anemia is nearly universal, typically resulting in a hemoglobin drop to 8–10 g/dL; management may include erythropoiesis-stimulating agents like epoetin alfa. Hypoxia is often reversible but requires proactive monitoring; clinicians recommend patients use home pulse oximeters and suggest drug interruption if oxygen saturation falls below 92%. Peripheral edema was also noted as a complication for patients with pre-existing heart failure. Over 90% of patients reported improved quality-of-life scores compared with everolimus, despite these class-specific toxicities.