What’s changing in oncology? Giredestrant, NGS, HER2-targeted therapy, FDA approvals & more

Giredestrant plus Everolimus in Advanced Breast Cancer

Mayer E … Rugo H. NEJM.

Take-home. Giredestrant plus everolimus significantly prolonged progression-free survival compared with standard endocrine therapy plus everolimus, with the greatest benefit observed in ESR1-mutated tumors.

This phase 3 trial evaluated giredestrant plus everolimus versus standard endocrine therapy plus everolimus in ER-positive/HER2-negative advanced breast cancer after CDK4/6 inhibitor treatment. Among patients with ESR1-mutated tumors, median progression-free survival was 10.0 versus 5.5 months (HR 0.38); in the overall population, it was 8.8 versus 5.5 months (HR 0.56). Adverse-event rates were similar between groups, with stomatitis, diarrhea, and anemia most common.

Read the paper: Giredestrant plus Everolimus in Advanced Breast Cancer (opens a new tab)

Effect of Screening with Multicancer Early-Detection Test on Late-Stage Cancer Diagnosis

Sasieni P … Swanton C. NEJM.

Take-home. Three rounds of multicancer blood-based screening did not reduce the incidence of stage III/IV cancers, although a possible reduction in stage IV disease warrants longer follow-up.

In this randomized English trial, 142,250 adults aged 50–77 were assigned to multicancer blood-based screening plus usual care or usual care alone. After three annual screening rounds, the primary endpoint (incidence of stage III/IV cancers across 12 prespecified cancers) did not differ significantly between groups (incidence rate ratio 1.03). Stage IV cancer incidence was lower with screening (IRR 0.86), but further follow-up is needed to clarify clinical significance and long-term effects.

Read the paper: Effect of Screening with Multicancer Early-Detection Test on Late-Stage Cancer Diagnosis (opens a new tab)See the highlight: Effect of Screening with Multicancer Early-Detection Test on Late-Stage Cancer Diagnosis

FDA Priority Review granted for durvalumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer

AstraZeneca.

The FDA granted Priority Review to AstraZeneca’s supplemental application for durvalumab plus enfortumab vedotin in cisplatin-ineligible or cisplatin-declining patients with muscle-invasive bladder cancer. The application is based on VOLGA, a phase III trial in which perioperative durvalumab plus neoadjuvant enfortumab vedotin significantly improved event-free and overall survival versus radical cystectomy with or without approved adjuvant therapy.

Read the announcement: FDA Priority Review granted for durvalumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer (opens a new tab)

FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component

FDA.

The FDA approved belzutifan plus lenvatinib for adults with advanced clear cell renal cell carcinoma after PD-1/PD-L1 inhibitor treatment, based on LITESPARK-011. In 747 patients, the combination significantly improved median PFS versus cabozantinib (14.6 vs 10.6 months; HR 0.74) and increased ORR (53% vs 40%). Final OS was not statistically significant (33.7 vs 28.6 months; HR 0.85). Key safety concerns include anemia, hypoxia, hypertension, and cardiac dysfunction.

Read the announcement: FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component (opens a new tab)

Efficacy and safety of HER2 directed therapies for advanced HER2-mutant non-small-cell lung cancer: a systematic review and meta-analysis

Li M … Soo R. JTO.

Take-home. HER2 TKIs showed higher response rates and fewer severe adverse events than ADCs, while ADC efficacy appeared preserved after prior TKI therapy.

This meta-analysis pooled seven prospective trials involving 916 patients with advanced HER2-mutant NSCLC. HER2 TKIs had a higher pooled objective response rate than ADCs (65% vs 57%), particularly for YVMA insertions (74% vs 57%). Responses were similar for non-YVMA TKD mutations and non-TKD mutations. ADC activity appeared preserved after prior TKI exposure, whereas TKI activity decreased after ADC treatment. Grade ≥3 adverse events were more frequent with ADCs.

Read the paper: Efficacy and safety of HER2 directed therapies for advanced HER2-mutant non-small-cell lung cancer: a systematic review and meta-analysis (opens a new tab)

Real-World Association Between Up-Front Next-Generation Sequencing and Overall Survival in Advanced Non–Small Cell Lung Cancer in the United States

Scott S … Levy B. JCO Precision Oncology.

Take-home. Up-front NGS before first-line therapy was associated with earlier targeted treatment and longer overall survival in advanced NSCLC.

This retrospective Flatiron Health study evaluated 13,139 patients with advanced NSCLC to assess whether timing of genomic testing influenced overall survival. Up-front NGS was associated with greater use of targeted therapy (22.6% vs 14.8% after first-line therapy) and longer median OS (20.9 months vs 17.5 months with non-NGS testing and 18.2 months with delayed NGS). Multivariable analyses suggested the survival association was primarily related to treatment selection.

Read the paper: Real-World Association Between Up-Front Next-Generation Sequencing and Overall Survival in Advanced Non–Small Cell Lung Cancer in the United States (opens a new tab)

Carboplatin in patients with metastatic castration-resistant prostate cancer harboring somatic or germline homologous recombination repair gene mutations: phase II single-arm trial (CIPHER)

Jain R … Batra A. ESMO Open.

Take-home. Carboplatin demonstrated meaningful antitumor activity in HRR-altered mCRPC, particularly with BRCA1/2 alterations, but substantial hematologic toxicity was common.

This phase II single-arm study evaluated carboplatin in 39 men with HRR-altered mCRPC previously treated with docetaxel and/or androgen-receptor pathway inhibitors. PSA50 response occurred in 41%, with median radiographic PFS of 4.53 months and response duration of 6.93 months. BRCA1/2-altered tumors showed particularly durable responses. Grade ≥3 adverse events occurred in 59%, mainly hematologic, while overall quality of life remained largely preserved during treatment.

Read the paper: Carboplatin in patients with metastatic castration-resistant prostate cancer harboring somatic or germline homologous recombination repair gene mutations: phase II single-arm trial (CIPHER) (opens a new tab)

Pretreatment Tumor NECTIN4 RNA Expression Is Associated with First-line Enfortumab Vedotin Plus Pembrolizumab Efficacy in Metastatic Urothelial Cancer

Chi B … Galsky M. European Urology.

Take-home. Pretreatment NECTIN4 expression and TMB may help identify patients more likely to benefit from first-line enfortumab vedotin plus pembrolizumab.

In a real-world cohort of 322 patients with metastatic urothelial cancer treated first-line with enfortumab vedotin plus pembrolizumab, high tumor NECTIN4 RNA expression and high TMB were each associated with better overall survival and response rates. NECTIN4 remained independently predictive after multivariable adjustment, while its association was not observed with pembrolizumab monotherapy. Patients with both low NECTIN4 and low TMB had the least favorable outcomes.

Read the paper: Pretreatment Tumor NECTIN4 RNA Expression Is Associated with First-line Enfortumab Vedotin Plus Pembrolizumab Efficacy in Metastatic Urothelial Cancer (opens a new tab)

Progression-free survival and objective response rate as a surrogate end point for overall survival in metastatic renal cell carcinoma: A systematic review and meta-analysis

Leong R … Srinivas R. Cancer.

Take-home. PFS and ORR correlate with OS in metastatic renal cell carcinoma, but their context-dependent and inconsistent performance means they cannot reliably substitute for OS.

This systematic review and meta-analysis included 62 randomized trials involving 24,518 patients with metastatic renal cell carcinoma. Treatment effects on PFS and ORR showed moderate correlations with OS, but neither endpoint demonstrated sufficiently consistent surrogacy to reliably predict survival benefit. Results varied across treatment settings and were often imprecise in subgroups, with limited non–clear cell representation. Substantial trial heterogeneity further limits interpretation and supports continued reliance on OS.

Read the paper: Progression-free survival and objective response rate as a surrogate end point for overall survival in metastatic renal cell carcinoma: A systematic review and meta-analysis (opens a new tab)

A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics

Van Renne N … Buisseret L. Cell Reports Medicine.

Take-home. Immune-rich tumor microenvironments predict better ICI outcomes, whereas fibrovascular and myeloid remodeling appear to drive resistance in advanced TNBC.

This study analyzed advanced triple-negative breast cancer treated with chemo-immunotherapy using transcriptomics, genomics, and spatial immune profiling. A transcriptomic PFS-risk signature stratified outcomes across ICI-treated cohorts. Immune-enriched tumors with organized lymphoid structures had better outcomes, whereas fibrotic and angiogenic tumors, often with PI3K alterations, had poorer outcomes. Early progression was associated with fibrovascular remodeling, macrophage expansion, and immunosuppressive signaling, identifying potential mechanisms and targets of ICI resistance.

Read the paper: A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics (opens a new tab)See the highlight: A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics

Evorpacept plus trastuzumab, ramucirumab and paclitaxel in HER2-positive gastric cancer: a randomized phase 2 trial

Shitara K … Lee KW. Nature Medicine.

Take-home. Evorpacept plus TRP showed promising response rates, especially in patients with retained HER2 positivity, but the study did not fully meet its predefined efficacy criteria.

ASPEN-06 evaluated evorpacept plus trastuzumab, ramucirumab and paclitaxel in pretreated HER2-overexpressing advanced gastric/GEJ cancer. The combination produced higher objective response rates than TRP alone, particularly in patients with HER2 positivity confirmed on a fresh biopsy. However, responses did not meet the prespecified statistical threshold versus the historical 30% benchmark in the overall population. Safety was broadly similar, although hematologic toxicities were more frequent with evorpacept.

Read the paper: Evorpacept plus trastuzumab, ramucirumab and paclitaxel in HER2-positive gastric cancer: a randomized phase 2 trial (opens a new tab)

Extended Follow-up of Botensilimab plus Balstilimab in an Expanded Cohort of Microsatellite-Stable Metastatic Colorectal Cancer without Active Liver Metastases

Schlechter B … Segal N. Clinical Cancer Research.

Take-home. Botensilimab plus balstilimab showed durable responses and encouraging survival in heavily pretreated MSS mCRC without active liver metastases, supporting further investigation.

In this phase Ib study, botensilimab plus balstilimab was evaluated in 123 heavily pretreated patients with MSS metastatic colorectal cancer without active liver metastases. After median 20.2-month follow-up, the objective response rate was 21%, with median progression-free survival of 4.0 months and overall survival of 21.2 months. Responses were durable, and efficacy remained similar in patients previously exposed to late-line therapies. Diarrhea and fatigue were the most common treatment-related toxicities.

Read the paper: Extended Follow-up of Botensilimab plus Balstilimab in an Expanded Cohort of Microsatellite-Stable Metastatic Colorectal Cancer without Active Liver Metastases (opens a new tab)

ESTRO recommendations for the use, planning and delivery of reirradiation in locally recurrent rectal cancer, endorsed by ASTRO

Paulen H … Muirhead R. Radiotherapy & Oncology.

Take-home. Reirradiation is a feasible component of multimodal treatment for locally recurrent rectal cancer, but careful patient selection, advanced radiation techniques, and attention to cumulative organ dose are essential.

These ESTRO recommendations provide practical guidance for reirradiation of locally recurrent rectal cancer, covering patient selection, treatment intent, dose, planning, and delivery. Recommended approaches include 30–40 Gy reirradiation, with SBRT for selected small recurrences and particle therapy at experienced centers. Cumulative normal-tissue dose should be assessed, with IMRT/VMAT and daily image guidance encouraged. However, evidence quality is generally low, so recommendations largely rely on expert consensus.

Read the paper: ESTRO recommendations for the use, planning and delivery of reirradiation in locally recurrent rectal cancer, endorsed by ASTRO (opens a new tab)