Xencor Presents Phase 1 Data for XmAb819 in Clear Cell Renal Cell Carcinoma

Analysis reveals significant industry trends and economic implications

Release Date

2025-10-27

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

Xencor announced initial results from the Phase 1 dose-escalation study of XmAb819, a first-in-class ENPP3 x CD3 bispecific T-cell engager, in patients with advanced clear cell renal cell carcinoma (ccRCC). The study showed that XmAb819 was well-tolerated and demonstrated anti-tumor activity in heavily pretreated patients. A 25% overall response rate was observed within the target dose range. The company is on track to select a recommended Phase 3 dose during 2026 and initiate a pivotal study in advanced ccRCC during 2027.

Key Highlights

  • XmAb819 is well-tolerated in heavily pretreated patients with advanced ccRCC.
  • 25% overall response rate (ORR) observed within the target dose range.
  • First dose-expansion cohort has been selected; dose escalation continues to identify dose for second expansion cohort.
  • XmAb819 demonstrated compelling anti-tumor activity and a well-tolerated safety profile.

Incidence and Prevalence

Global Incidence and Prevalence of Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for approximately 85-90% of all kidney cancers and 2-4% of all cancers globally. According to the most recent data from 2022, there were approximately 337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths.

The Global Burden of Disease (GBD) 2021 study revealed that kidney cancer contributed significantly to global cancer morbidity and mortality. From 2000 to 2021, the age-standardized incidence rate (ASIR) for RCC increased by an average annual percent change of 0.15% (95% confidence interval: 0.07-0.23%), while the age-standardized death rates (ASDRs) decreased for all three urological cancers.

The incidence of kidney cancer has been increasing worldwide in recent years, with rates increasing by 2-3% per decade globally. By 2021, there were approximately 720,000 new cases of kidney cancer associated with high BMI globally, a significant rise from roughly 500,000 cases in 1990.

Geographic distribution of RCC shows significant variation. The incidence of kidney cancer is higher in high to middle-SDI (sociodemographic index) regions compared to lower SDI regions. North America and Western Europe have the highest disease burden, with Belarus having the highest incidence. The Czech Republic and other geographically neighboring countries in Central Europe, including the Slovak Republic, have the highest worldwide rates.

In Africa and the Middle East, the age-standardized incidence for RCC is 1.8-4.8/100,000 for males and 1.2-2.2/100,000 for females. Kidney cancer is relatively uncommon in Asia compared with the West, but its incidence is increasing in more developed Asian nations. In the Gulf Cooperation Council (GCC) countries, 4,078 cases of renal cell carcinoma were diagnosed from 1998 to 2012, with urological cancers comprising 9.4% of all cases with an incidence rate of 16.1% in males and 3.2% in females.

In the United States, the age-standardized incidence rates per 100,000 for kidney and pelvis cancers were 22.03 for men and 11.14 for women (2000-2019), with Non-Hispanic Black men having the highest ASIR at 24.53 per 100,000.

There is a notable gender disparity in RCC prevalence, with males experiencing higher rates compared to females across all age brackets. The probability of developing kidney cancer was generally higher in males (0.79% between ages 30-70) than in females (0.41%). Incidence rates were found to peak among middle-aged individuals.

By 2030, incidence of kidney cancer is projected to increase substantially in high SDI countries, followed by middle SDI, low-middle SDI, and low SDI countries. Latin America, Asia, and Africa are projected to see an increase in incidence as nations transition to a Western lifestyle.

Risk factors contributing to the rising incidence include smoking and high body mass index, which were identified as the leading causes of risk-attributable deaths of urological cancers, including RCC.

Key Unmet Needs in Renal Cell Carcinoma Treatment

Clear cell renal cell carcinoma (ccRCC) remains one of the most common and lethal urologic cancers with low survival rates in advanced stages and increasing morbidity and mortality worldwide. Despite significant progress in diagnosis and treatment, several critical unmet needs persist.

Treatment Limitations

Current approaches including drug-targeted therapy and immunotherapy face substantial challenges: - Drug resistance development - Unsatisfactory long-term benefits - Adverse effects - Limited objective response rates for metastatic disease - Significant variation in efficacy of immune checkpoint blockade (ICB) therapy - Lack of reliable markers for patient selection - Limited duration of disease control

ccRCC is characterized by extreme heterogeneity and metastatic tendency, limiting the effectiveness of targeted and immune therapies. Additionally, ccRCC shows poor sensitivity to both radiotherapy and chemotherapy.

Patient Populations Being Targeted

Research is focusing on several specific patient populations: - ccRCC patients (comprising approximately 75% of renal cell carcinomas) - Patients with advanced tumor stages and larger tumors - Metastatic renal cancer patients - Patients with different risk profiles based on pyroptosis-related genes - Patients categorized by cuprotosis marker gene enrichment levels - Patients with varying basement membrane gene (BMG) expression patterns - Individuals with specific CK1δ/ε expression levels - Patients with particular HVEM and CD160 gene polymorphisms - Patients with sarcopenia (defined as ALT < 17 IU/L) - Elderly RCC patients (mean age 65.6 ± 13.3 years) - Non-clear cell RCC patients, who are typically under-represented in clinical trials

Promising Research Directions

To address these unmet needs, research is exploring: - Novel cell death mechanisms including copper-induced cell death (cuprotosis) and pyroptosis - Circular RNAs and long non-coding RNAs as potential biomarkers - Molecular biomarkers such as CXCR3, LAG3, TUBA1C, and CWH43 - Prognostic models based on immune cell infiltration and gene expression - Potential tumor suppressor genes as prognostic biomarkers and therapeutic targets - Improved adjuvant therapy decision-making for localized RCC

Critical Challenges

The field faces several ongoing challenges: - Unremarkable early symptoms leading to delayed diagnosis - Proneness to postoperative metastasis or recurrence - Immunosuppressive tumor microenvironments contributing to treatment resistance - Ambiguity about which patients benefit most from adjuvant therapy - Prevention of adverse events and medication resistance - Identifying appropriate biomarkers for liquid biopsy to identify high-risk patients

These unmet needs highlight the urgent requirement for novel therapeutic targets and improved patient stratification to overcome current limitations and enhance outcomes for RCC patients.

Recent Studies

Recent Clinical Trials for Renal Cell Carcinoma

NIVOREN Trial (2023)

  • Intervention: Nivolumab after failure of antiangiogenic agents

  • Efficacy:

  • Median OS: 17.9 months in patients with bone metastases versus 26.1 months in patients without

  • Median PFS: 2.8 months (with bone metastases) versus 4.6 months (without)

  • ORR: 14.8% (with bone metastases) versus 23.3% (without)

  • Safety: Not specifically detailed in this trial

INMUNOSUN Trial (2022)

  • Intervention: Sunitinib as second-line treatment after immune checkpoint inhibitor therapy

  • Efficacy:

  • ORR: 19.0% (4 patients with partial responses)

  • Stable disease: 67% (14 patients)

  • Clinical benefit: 85.7%

  • Median PFS: 5.6 months

  • Median OS: 23.5 months

  • Safety:

  • Most frequent adverse events: diarrhea (52%), dysgeusia (38%), palmar-plantar erythrodysesthesia (38%), hypertension (38%)

  • One patient exhibited grade 5 pancytopenia

  • 11 patients experienced grade 3 adverse events

Anlotinib Study (2020)

  • Intervention: Anlotinib (oral multi-target tyrosine kinase inhibitor)

  • Efficacy:

  • Partial response: 30.6% (11 patients)

  • Stable disease: 66.7% (24 patients)

  • Disease control rate: 97.2%

  • Median PFS: 12.6 months

  • 1-year survival rate: 80.6%

  • Median survival time: 22.2 months

  • Safety:

  • Most common grade 3-4 adverse events: hypertension (19.4%), hand-foot skin reaction (11.1%), proteinuria (5.6%), anemia (5.6%)

A2AR Antagonist Trial (2021)

  • Intervention: A2AR antagonist (small-molecule) alone and in combination with anti-PD-L1 antibody

  • Efficacy:

  • Clinical responses observed both as monotherapy and in combination with anti-PD-L1

  • Responses seen in subjects who had progressed on PD-1/PD-L1 inhibitors

  • Durable clinical benefit associated with increased recruitment of CD8 T cells

  • Safety: The molecule "safely blocked adenosine signaling in vivo"

Talazoparib plus Avelumab Trial (2023)

  • Intervention: Talazoparib (PARPi) plus avelumab (ICB)

  • Efficacy:

  • ORR: 0% in both cohorts

  • Stable disease: 7/9 evaluable patients in VHL-altered cohort, 2/8 in other cohort

  • Median PFS: 3.5 months (VHL-altered), 1.2 months (other cohort)

  • Safety:

  • Most common treatment-related adverse events: fatigue (61%), anemia (28%), nausea (22%), headache (22%)

  • Seven grade 3-4 events, no grade 5 events

  • Combination found to be safe but not effective