Bevacizumab-Erlotinib Combination Shows Remarkable 72% Response Rate in Rare HLRCC-Associated Kidney Cancer
核心洞察
A phase 2 trial demonstrated that bevacizumab plus erlotinib achieved a 72% overall response rate in patients with hereditary leiomyomatosis and renal cell cancer (搜索) (HLRCC)-associated papillary renal cell carcinoma (搜索).
The combination therapy extended median overall survival to 44.6 months in HLRCC patients, nearly doubling historical survival expectations for this aggressive cancer variant.
In sporadic papillary renal cell carcinoma (搜索) patients, the combination showed moderate activity with a 35% response rate and 18.2 months median overall survival.
A combination of bevacizumab and erlotinib demonstrated remarkable antitumor activity in patients with advanced hereditary leiomyomatosis and renal cell cancer (搜索) (HLRCC)-associated papillary renal cell carcinoma (搜索), achieving a 72% overall response rate and extending median overall survival to 44.6 months, according to results from a phase 2 trial published in the New England Journal of Medicine.
The open-label study (NCT01130519) enrolled 83 patients between May 2010 and May 2019, including 43 patients with HLRCC-associated papillary renal cell carcinoma (搜索) and 40 patients with sporadic disease. All patients received bevacizumab at 10 mg/kg intravenously every 2 weeks combined with oral erlotinib at 150 mg once daily.
Strong Efficacy in HLRCC-Associated Disease
Among evaluable patients with HLRCC-associated papillary renal cell carcinoma (搜索), the confirmed overall response rate reached 72% (95% CI, 57%-83%), including 2 patients (5%) who achieved complete responses. The median time to response was 1.8 months (range, 1.7 to 18.3 months). Responses were observed across all International Metastatic RCC Database Consortium (IMDC) risk categories, with response rates of 64% in favorable risk, 75% in intermediate risk, and 75% in poor risk patients.
"This study showed that the combination of bevacizumab and erlotinib was highly active in advanced HLRCC-associated papillary renal-cell carcinoma," noted lead study author Ramaprasad Srinivasan, MD, PhD, a senior investigator in the Urologic Oncology Branch of the National Cancer Institute.
The survival outcomes were particularly encouraging, with a median progression-free survival of 21.1 months (95% CI, 15.6-26.6) and median overall survival of 44.6 months (95% CI, 32.7-not estimable) after a median follow-up of 71.9 months. This represents a substantial improvement over historical outcomes, as HLRCC-associated papillary renal cell carcinoma (搜索) typically carries a median overall survival of 16 to 21 months in retrospective series.
Moderate Activity in Sporadic Disease
In patients with sporadic papillary renal cell carcinoma (搜索), the combination showed more modest but still meaningful activity. The confirmed overall response rate was 35% (95% CI, 22%-51%), with a median time to response of 1.8 months (range, 1.7 to 7.3 months). Response rates varied by IMDC risk category: 67% in favorable risk, 31% in intermediate risk, and 38% in poor risk patients.
Survival outcomes in the sporadic cohort included a median progression-free survival of 8.9 months (95% CI, 5.5-18.3) and median overall survival of 18.2 months (95% CI, 12.6-29.3) after a median follow-up of 63.6 months.
Patient Characteristics and Prior Treatments
The HLRCC-associated cohort included 30 men and 13 women with a median age of 43 years (range, 19-74). The sporadic papillary RCC group comprised 26 men and 14 women with a median age of 55.5 years (range, 24-74). All patients had metastatic disease at baseline.
Prior systemic therapy was less common in the HLRCC-associated group, with 21% having received previous treatment compared to 45% in the sporadic group. Among HLRCC patients, 19% had previously received at least one VEGFR (搜索) tyrosine kinase inhibitor, while 35% of sporadic patients had prior VEGFR TKI exposure.
Safety Profile
All patients experienced at least one treatment-related adverse event, with 52% developing grade 3 or higher events. The most common adverse events of any grade included acneiform rash (93%), diarrhea (89%), and proteinuria (78%). Grade 3 or higher events were led by hypertension (34%) and proteinuria (17%).
Dose modifications were primarily required for erlotinib, with reductions needed in 29% of patients and permanent discontinuation in 1% due to grade 3 cutaneous toxicity. Bevacizumab discontinuation occurred in 4% of patients, including two cases of acute coronary syndrome and one case of bronchopulmonary hemorrhage.
Clinical Implications
The findings address a significant unmet medical need, as few effective treatment options exist for papillary renal cell carcinoma (搜索) variants. "Few effective options exist for other variants of renal-cell carcinoma, which is exemplified by HLRCC-associated papillary renal-cell carcinoma," the authors explained, noting that this variant is typically associated with an aggressive clinical course.
"The median survival now is almost 4 years with this combination treatment," concluded W. Marston Linehan, MD, in a news release. "We're thrilled about that. This has now become a standard treatment of this disorder worldwide."
The researchers noted that further investigation is warranted to understand resistance mechanisms, and a phase 2 trial (NCT04981509) is ongoing to evaluate the combination with the addition of atezolizumab.