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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. 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). 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]. 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. [Display omitted] • Amivantamab-lazertinib significantly improved PFS in patients with detectable ctDNA at baseline versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients without ctDNA clearance at C3D1 versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with TP53 co-mutations versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with liver metastases versus osimertinib. • Eighty-nine percent of patients with analyzable ctDNA by NGS from MARIPOSA had at least one high-risk baseline feature. [ABSTRACT FROM AUTHOR]

Initial reports from the S elective P ersonalized R adioimmunotherapy for Locally Advanced N SCLC T rial (SPRINT) indicated that patients with high PD-L1 expression can be treated safely and effectively with immunotherapy and radiotherapy (RT). Here, we compare patient-reported outcomes (PROs) from SPRINT to PROs from patients who were treated with standard concurrent chemoradiotherapy on contemporary prospective trials to test the hypothesis that the SPRINT approach yields favorable patient-reported outcomes. SPRINT participants with PD-L1 tumor proportion score ≥ 50% were treated with "PembroRT": three 21-day cycles of induction pembrolizumab, a four-week course of risk-adapted and de-intensified RT (55 Gy to tumors or lymph nodes measuring 20 cc or larger and 48 Gy to smaller lesions, all in 20 fractions and without concurrent chemotherapy), and up to 13 cycles of consolidation pembrolizumab. SPRINT participants with lower PD-L1 expression and participants on the control arm of NCT03481114 were treated with "ChemoRT": a standard RT dose of 60 Gy in 30 fractions with concurrent weekly carboplatin and paclitaxel and standard adjuvant therapy (e.g., durvalumab). Participants in both trials completed a 12-item PRO-CTCAE survey at baseline, every two weeks during RT, and at follow-up visits. Study participants who completed the planned RT course and completed at least two PRO-CTCAE surveys were included in this analysis. Peak PRO-CTCAE grades recorded up to 90 days after RT completion were compared across treatment cohorts using Kruskal-Wallis testing. Multivariable logistic regression models were utilized to evaluate predictors of grade 2+ patient-reported toxicity. Kaplan-Meier curves and log rank testing were utilized to compare progression-free survival (PFS) and overall survival (OS) across treatment cohorts. The PembroRT cohort included 19 patients, and the ChemoRT cohort included 26 patients. Mean esophagus and lung doses were significantly lower in the PembroRT cohort, with median values approximately 5 Gy lower than in the ChemoRT group. Average PRO-CTCAE grades were numerically higher in the ChemoRT group for all 12 symptoms, with statistically significant differences observed for cough, wheezing, dermatitis, dizziness, anxiety, and depression. Multivariable models demonstrated that patient-reported toxicity was generally not associated with chemotherapy receipt, while several patient-reported adverse events were associated with organ at risk doses. For example, grade 2+ dysphagia incidence was associated with mean esophageal dose. The PembroRT cohort had superior 3-year rates of PFS (61% v. 23%, P = 0.033) and OS (88% v. 49%, P = 0.013). Compared to standard chemoradiotherapy, the SPRINT treatment approach, which utilizes induction immunotherapy to reduce target volumes and risk-adapted RT, can improve patient-reported outcomes without compromising clinical outcomes. [ABSTRACT FROM AUTHOR]

Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy (chemoRT), which is usually followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Patients with AJCC version 8 stage III NSCLC or unresectable stage II NSCLC and ECOG performance status 0-1 were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) ≥ 50% received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. Subjects with PD-L1 TPS < 50% received concurrent chemoRT, and adjuvant durvalumab was recommended for patients without disease progression. The primary study endpoint was one-year progression-free survival (PFS) for subjects treated with pembrolizumab and radiotherapy (pembroRT), which we hypothesized would exceed 65%. Other study endpoints included 1-year overall survival (OS) and rates of clinician-scored (CTCAE v. 4.03) and patient-reported (PRO-CTCAE) adverse events observed over one year. Twenty-five subjects with PD-L1 TPS ≥ 50% and 12 subjects with PD-L1 TPS < 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 70. Twenty-four subjects had stage II-IIIA disease, and 13 had stage IIIB-IIIC disease. Except for PD-L1 TPS, subject characteristics did not differ significantly across treatment groups. Ten out of the 12 subjects with ChemoRT received adjuvant durvalumab, and one received adjuvant osimertinib for EGFR mutation. The median follow-up duration is 15 months. Compared to patients treated with chemoRT, treatment with pembroRT has yielded numerically higher 1-year PFS (72% v. 46%, log rank p=0.232) and OS (91% v. 73%, log rank p=0.213) rates. Similar rates of grade 3 physician-scored adverse events have been observed with pembroRT (24%) and chemoRT (25%). Less severe patient-reported adverse events occurred with pembroRT compared to chemoRT (See Table). Treatment with pembrolizumab and risk-adapted radiotherapy without chemotherapy is a promising approach for LA-NSCLC patients with PD-L1 TPS ≥ 50%. In addition to yielding high disease control rates, this strategy appears to reduce patient-reported adverse events compared to standard chemoRT and adjuvant therapy. [ABSTRACT FROM AUTHOR]