Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Correlation of Tumor Immunohistochemistry with Dynamic Contrast-Enhanced and DSC-MRI Parameters in Patients with Gliomas.

BACKGROUND AND PURPOSE: Tumor CBV is a prognostic and predictive marker for patients with gliomas. Tumor CBV can be measured noninvasively with different MR imaging techniques; however, it is not clear which of these techniques most closely reflects histologically-measured tumor CBV. Our aim was to investigate the correlations between dynamic contrast-enhanced and DSC-MR imaging parameters and immunohistochemistry in patients with gliomas. MATERIALS AND METHODS: Forty-three patients with a new diagnosis of glioma underwent a preoperative MR imaging examination with dynamic contrast-enhanced and DSC sequences. Unnormalized and normalized cerebral blood volume was obtained from DSC MR imaging. Two sets of plasma volume and volume transfer constant maps were obtained from dynamic contrast-enhanced MR imaging. Plasma volume obtained from the phase-derived vascular input function and bookend T1 mapping (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function and bookend T1 mapping (Ktrans_Φ) were determined. Plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (Ktrans_SI) were acquired, without T1 mapping. Using CD34 staining, we measured microvessel density and microvessel area within 3 representative areas of the resected tumor specimen. The Mann-Whitney U test was used to test for differences according to grade and degree of enhancement. The Spearman correlation was performed to determine the relationship between dynamic contrast-enhanced and DSC parameters and histopathologic measurements. RESULTS: Microvessel area, microvessel density, dynamic contrast-enhanced, and DSC-MR imaging parameters varied according to the grade and degree of enhancement (P < .05). A strong correlation was found between microvessel area and Vp_Φ and between microvessel area and unnormalized blood volume (rs ≥ 0.61). A moderate correlation was found between microvessel area and normalized blood volume, microvessel area and Vp_SI, microvessel area and Ktrans_Φ, microvessel area and Ktrans_SI, microvessel density and Vp_Φ, microvessel density and unnormalized blood volume, and microvessel density and normalized blood volume (0.44 ≤ rs ≤ 0.57). A weaker correlation was found between microvessel density and Ktrans_Φ and between microvessel density and Ktrans_SI (rs ≤ 0.41). CONCLUSIONS: With dynamic contrast-enhanced MR imaging, use of a phase-derived vascular input function and bookend T1 mapping improves the correlation between immunohistochemistry and plasma volume, but not between immunohistochemistry and the volume transfer constant. With DSC-MR imaging, normalization of tumor CBV could decrease the correlation with microvessel area.

Comparison of the Diagnostic Accuracy of DSC- and Dynamic Contrast-Enhanced MRI in the Preoperative Grading of Astrocytomas.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging parameters can be biased by poor measurement of the vascular input function. We have compared the diagnostic accuracy of dynamic contrast-enhanced MR imaging by using a phase-derived vascular input function and "bookend" T1 measurements with DSC MR imaging for preoperative grading of astrocytomas. MATERIALS AND METHODS: This prospective study included 48 patients with a new pathologic diagnosis of an astrocytoma. Preoperative MR imaging was performed at 3T, which included 2 injections of 5-mL gadobutrol for dynamic contrast-enhanced and DSC MR imaging. During dynamic contrast-enhanced MR imaging, both magnitude and phase images were acquired to estimate plasma volume obtained from phase-derived vascular input function (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function (K(trans)_Φ) as well as plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (K(trans)_SI). From DSC MR imaging, corrected relative CBV was computed. Four ROIs were placed over the solid part of the tumor, and the highest value among the ROIs was recorded. A Mann-Whitney U test was used to test for difference between grades. Diagnostic accuracy was assessed by using receiver operating characteristic analysis. RESULTS: Vp_ Φ and K(trans)_Φ values were lower for grade II compared with grade III astrocytomas (P < .05). Vp_SI and K(trans)_SI were not significantly different between grade II and grade III astrocytomas (P = .08-0.15). Relative CBV and dynamic contrast-enhanced MR imaging parameters except for K(trans)_SI were lower for grade III compared with grade IV (P ≤ .05). In differentiating low- and high-grade astrocytomas, we found no statistically significant difference in diagnostic accuracy between relative CBV and dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: In the preoperative grading of astrocytomas, the diagnostic accuracy of dynamic contrast-enhanced MR imaging parameters is similar to that of relative CBV.