Yiwen Luo

PURPOSE Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.

PURPOSE Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR -mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837 ). METHODS Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. RESULTS Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. CONCLUSION Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

LBA9000 Background: EGFR TKIs are standard 1L therapy for metastatic NSCLC with sensitizing EGFR mutations; however, most patients (pts) ultimately experience PD. We report the protocol-specified final analysis (FA) from the randomized, double-blind, phase 3 KEYNOTE-789 study of pemetrexed (pem) and platinum-based chemotherapy (chemo) with or without pembrolizumab (pembro) as subsequent therapy for pts with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (NCT03515837). Methods: Adults with histologically or cytologically confirmed stage IV nonsquamous NSCLC, ECOG PS of 0 or 1, documented DEL19 or L858R EGFR mutation, and progression after EGFR TKI treatment were enrolled. Pts were randomized 1:1 to 35 cycles of pembro 200 mg Q3W or placebo (pbo) Q3W plus 4 cycles of pem and carboplatin or cisplatin Q3W followed by maintenance pem. Randomization was stratified by PD-L1 TPS (<50% vs ≥50%), prior osimertinib (yes vs no), and region (East Asia vs not East Asia). Dual primary endpoints were PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. ORR and DOR per RECIST v1.1 by BICR and safety were secondary endpoints. Final PFS testing was completed at the second interim analysis (IA2; data cutoff, Dec 3, 2021); all other endpoints were assessed at FA (data cutoff, Jan 17, 2023). Efficacy boundaries based on actual observed events were 1-sided P = 0.0117 for PFS (IA2) and P = 0.0118 for OS (FA). Results: 492 pts were randomized to pembro + chemo (n = 245) or pbo + chemo (n = 247). At IA2, median PFS (95% CI) was 5.6 (5.5–5.8) mo with pembro + chemo vs 5.5 (5.4–5.6) mo with pbo + chemo; HR 0.80 (95% CI, 0.65–0.97); P = 0.0122; and the results did not reach statistical significance. Median (range) time from randomization to data cutoff at FA (Jan 17, 2023) was 42.0 (29.5–53.9) mo. At FA, median OS (95% CI) was 15.9 (13.7–18.8) vs 14.7 (12.7–17.1) mo. While the HR for OS (0.84 [95% CI, 0.69–1.02]; P = 0.0362) favored pembro + chemo vs pbo + chemo, it did not reach statistical significance. OS rates at 12-mo were 61.6% vs 59.4% and at 24-mo were 30.6% vs 26.4%. HR for OS was similar in PD-L1 TPS ≥50% (HR, 0.84) and TPS <50% groups (HR, 0.85). ORR (95% CI) in ITT was 29.0% (23.4%–35.1%) with pembro + chemo vs 27.1% (21.7%–33.1%) with pbo + chemo. Median DOR was 6.3 (2.3 to 40.8+) mo vs 5.6 (1.8+ to 40.6+) mo. Grade ≥3 treatment-related AEs occurred in 43.7% of pts in pembro + chemo arm and 38.6% in pbo + chemo arm; grade 5 AEs occurred in 0.4% vs 0.8%. Grade ≥3 immune-mediated AEs and infusion reactions occurred in 4.5% of pts in the pembro + chemo arm and 2.0% in the pbo + chemo arm; 0.4% vs 0% had grade 5 events. Conclusions: In the KEYNOTE-789 study, addition of pembro to chemo in pts with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS and OS in comparison to pbo + chemo. AEs were manageable in both arms, and no new safety signals were identified. Clinical trial information: NCT03820986 .

BACKGROUND: Cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants that have been associated with lower birthweight. Although some essential metals may mitigate exposure, data are inconsistent. This study sought to evaluate the relationship between toxic metals, nutrient combinations and birthweight among 275 mother-child pairs. METHODS: Non-essential metals, Cd, Pb, As, and essential metals, iron (Fe), zinc (Zn), selenium (Se), copper (Cu), calcium (Ca), magnesium (Mg), and manganese (Mn) were measured in maternal whole blood obtained during the first trimester using inductively coupled plasma mass spectrometry. Folate concentrations were measured by microbial assay. Birthweight was obtained from medical records. We used quantile regression to evaluate the association between toxic metals and nutrients due to their underlying wedge-shaped relationship. Ordinary linear regression was used to evaluate associations between birth weight and toxic metals. RESULTS: After multivariate adjustment, the negative association between Pb or Cd and a combination of Fe, Se, Ca and folate was robust, persistent and dose-dependent (p < 0.05). However, a combination of Zn, Cu, Mn and Mg was positively associated with Pb and Cd levels. While prenatal blood Cd and Pb were also associated with lower birthweight. Fe, Se, Ca and folate did not modify these associations. CONCLUSION: Small sample size and cross-sectional design notwithstanding, the robust and persistent negative associations between some, but not all, nutrient combinations with these ubiquitous environmental contaminants suggest that only some recommended nutrient combinations may mitigate toxic metal exposure in chronically exposed populations. Larger longitudinal studies are required to confirm these findings.