The Targeted Pulse: Advancements in CLL, RCC, CRC, and More

This week has brought forth significant strides in the oncology landscape, with promising new data and regulatory approvals offering renewed hope for patients battling various cancers. From novel Bruton tyrosine kinase inhibitors (BTKi) in chronic lymphocytic leukemia (CLL) to groundbreaking immunotherapies in renal cell carcinoma (RCC) and colorectal cancer (CRC), the focus remains on improving patient outcomes through targeted and more tolerable treatments.

Pirtobrutinib and Zanubrutinib Reshape CLL Treatment Paradigms

Two major developments in CLL highlight the ongoing evolution of treatment strategies. Findings from the phase 3 BRUIN CLL-321 study (NCT04666038) demonstrate that pirtobrutinib (Jaypirca) significantly improves progression-free survival (PFS) and time to next treatment (TTNT) in patients with relapsed/refractory CLL/small lymphocytic lymphoma (SLL) previously treated with covalent BTKi. With a median PFS of 14 months compared with 8.7 months for standard options like idelalisib (Zydelig)/rituximab (Rituxan) or bendamustine/rituximab, pirtobrutinib offers a favorable tolerability profile, representing a crucial new option for this heavily pretreated population. Read more about the study here.

In a related advancement, a matching-adjusted indirect comparison analysis presented at the 2025 European Hematology Association Congress indicated that zanubrutinib (Brukinsa) shows a superior PFS benefit over the combination of acalabrutinib (Calquence) plus venetoclax (Venclexta) in patients with CLL. This analysis, comparing data from the SEQUOIA (NCT3336333) and AMPLIFY (NCT0386261) trials, found a significant hazard ratio favoring zanubrutinib, suggesting its potential as a more effective first-line option for treatment-naive patients with CLL, especially those without 17p deletions or TP53 mutations. Learn more here.

Navigating the Complexities of Non–Clear Cell Renal Cell Carcinoma

The treatment landscape for non–clear cell RCC (nccRCC), which accounts for approximately 25% of RCC cases, continues to evolve. Historically challenging due to patient exclusion from many clinical trials, recent data offer new avenues. The SUNNIFORECAST study (NCT03075423) showed that ipilimumab (Yervoy) plus nivolumab (Opdivo) as frontline therapy for advanced nccRCC achieved a 12-month overall survival rate of 78% compared with 68% with standard of care, primarily VEGF-targeted TKI monotherapy. While not reaching statistical significance for median OS, this study marks progress in a challenging disease. Combinations of TKIs like cabozantinib (Cabometyx) or lenvatinib (Lenvima) with nivolumab or pembrolizumab (Keytruda) are also showing encouraging activity, particularly in papillary RCC, the most common nccRCC subtype. For rarer forms like collecting duct carcinoma and renal medullary carcinoma, platinum-based chemotherapy remains a cornerstone, with agents like cabozantinib also demonstrating efficacy in collecting duct carcinoma. Read more about these developments here.

FDA Approvals and Promising Combinations in NSCLC and CRC

The FDA has granted accelerated approval to datopotamab deruxtecan-dlnk (Datroway; Dato-DXd) in adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) who have received previous systemic therapies. This TROP2-directed antibody-drug conjugate showcased a confirmed overall response rate of 45% with a median duration of response of 6.5 months in pooled analyses from the TROPION-Lung05 (NCT04484142) and TROPION-Lung01(NCT04656652) trials. This approval offers a much-needed chemotherapy-free option for patients with limited post progression treatments, albeit with important boxed warnings for interstitial lung disease and ocular toxicity. Read more about the approval here.

Finally, new data from the phase 3 STELLAR-303 pivotal trial (NCT05425940) indicate that zanzalintinib (XL092) in combination with atezolizumab (Tecentriq) significantly improved overall survival compared with regorafenib in patients with previously treated metastatic CRC. This combination of an investigational TKI and an immune checkpoint inhibitor underscores the power of synergistic approaches in overcoming treatment resistance and enhancing patient survival in non-microsatellite instability-high metastatic CRC. The safety profile remained consistent with previously reported data, without new safety signals identified. Check out all of the study details here.

These advancements represent a dynamic week in oncology, bringing forward novel therapies and combination strategies that hold the potential to significantly impact patient care and outcomes across multiple cancer types.