Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system. In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model. A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P = 0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively. Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.).

PURPOSE: Lazertinib is a potent, CNS-penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This global, phase III study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were 18 years and older with no previous systemic anticancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomly assigned 1:1 to lazertinib 240 mg once daily orally or gefitinib 250 mg once daily orally, stratified by mutation status and race. The primary end point was investigator-assessed progression-free survival (PFS) by RECIST v1.1. RESULTS: Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 v 9.7 months; hazard ratio [HR], 0.45; 95% CI, 0.34 to 0.58; P < .001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P = .116). Observed safety of both treatments was consistent with their previously reported safety profiles. CONCLUSION: Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.

Background/Aims: Previously advanced lung cancer inflammation index (ALI) has been demonstrated to have prognostic utility in the stratification of patients into distinctive survival groups, but the prognostic value of ALI has never been explored in the setting of locally advanced pancreatic carcinomas (LAPC) treated with concurrent chemoradiotherapy (CCRT). Hence, we aimed to investigate the prognostic value of pre-treatment ALI in LAPC patients who underwent radical CCRT. Methods: Present retrospective cohort analysis incorporated 141 LAPC patients who received radical CCRT. Accessibility of baseline ALI cutoff(s) impacting survival outcomes was sought by receiver operating characteristic (ROC) curve analysis. Interaction between the ALI and overall- (OS) and progression-free survival (PFS) comprised our primary and secondary endpoints, respectively. Results: At a median follow-up of 14.4 months (range: 3.2–74.2), the median PFS and OS were 7.5 (%95 CI: 5.9–9.1) and 14.6 months (%95 CI: 11.6–17.6), respectively. ROC curve analyses set the ideal ALI cutoff value at 25.3 (AUC: 75.6%; sensitivity: 72.7%; specificity: 70.3%) that exhibited significant associations with both the OS and PFS results. Patient stratification into two groups per ALI [≤25.3 (N=75) versus>25.3 (N=66)] showed that the ALI>25.3 group had significantly superior median OS (25.8 versus 11.4 months; P<0.001) and PFS (15.9 versus 6.0 months; P<0.001) durations than its ALI≤25.3 counterpart. Other factors exhibiting significantly better OS and PFS rates were N₀ stage (versus N1; P90 U/mL; P<0.05 for each endpoint), respectively. These three factors were additionally asserted to be independent indicators of longer OS (P<0.05 for each) and PFS (P<0.05 for each) in multivariate analyses. Conclusion: Results of this hypothesis-generating research proposed the pre-CCRT ALI as a novel robust associate of OS and PFS outcomes for LAPC patients undergoing CCRT.

Background. We investigated the prognostic significance of pretreatment systemic inflammation response index (SIRI) in locally advanced pancreatic carcinoma (LAPC) patients treated with concurrent chemoradiotherapy (CRT). Methods. Present retrospective cohort analysis investigated consecutive 154 LAPC patients who received radical CRT. The SIRI was defined as: SIRI=neutrophil×monocyte/lymphocytecounts. Ideal SIRI cutoff(s) influencing overall survival (OS) and progression-free survival (PFS) results were sought by using receiver operating characteristic (ROC) curve analysis. The primary endpoint was the interaction between the SIRI and OS results. Results. The median follow-up, PFS, and OS durations were 14.3 (range: 2.9-74.6), 7.9 [%95 confidence interval (CI): 5.7-10.1), and 14.7 months (%95 CI: 11.4-18.0) for the entire cohort, respectively. ROC curve analyses determined the ideal SIRI cutoff that exhibiting a significant link with OS and PFS outcomes at the rounded 1.6 point (AUC: 74.3%; sensitivity: 73.8%; specificity: 70.1%).The SIRI 90 U/mL) appeared as the other significant associates of better OS and PFS in univariate analyses, yet the results of multivariate analyses confirmed the SIRI <1.6 as the independent indicator of superior OS and PFS (P<0.001 for each). Conclusion. Pretreatment SIRI is a novel independent prognosticator that may further enhance the conventional tumor-node-metastases staging system in a more precise prediction of the OS and PFS outcomes of LAPC patients after radical CRT.

Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy demonstrated greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA demonstrated encouraging clinical activity in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who had received previous treatment. This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) vs. placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary endpoint was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. Based on the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary endpoint). A total of 153 patients were randomized to either BA (n=75) or durvalumab groups (n=78). Median PFS was 12.8 months vs. 14.6 months (stratified hazard ratio: 1.48 [95% confidence interval, 0.69-3.17], in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% vs. 32.1%) and disease control rate (66.7% vs. 70.5%) were similar between the two groups. Any grade treatment-emergent adverse events occurred in 94.6% vs. 96.1% of patients in the BA vs. durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). BA with cCRT followed by BA demonstrated no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.