9502 Background: First-line therapy for advanced NSCLC includes PD-1 checkpoint inhibitor (ICI) monotherapy, and in combination with chemotherapy. Combination ICI have also demonstrated better survival compared to chemotherapy (CM-227). In CCTG BR.34, we compared overall survival (OS) in patients with advanced NSCLC receiving first-line durvalumab plus tremelimumab (DT) with or without platinum doublet chemotherapy (CT). Methods: This international, open-label, randomized trial accrued 301 participants from Canada and Australia, with stage IV NSCLC, EGFR/ALK wildtype, ECOG PS 0/1. Patients were randomized to DT for 4 cycles or DT+CT (pemetrexed- or gemcitabine-platinum), with ongoing D or D + pemetrexed (non-squamous) maintenance until disease progression. Stratification factors included histology, stage IVA v. IVB and smoking status. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR = CR + PR) and adverse events (AEs). Results: At a median follow up of 16.6 months, no significant difference in OS was seen between the two treatment arms, with a median OS of 16.6 months with DT+CT v. 14.1 months with DT, (estimated HR 0.88, 90% CI 0.67-1.16). PFS was significantly improved in the DT+CT arm (stratified HR 0.67, 95% CI 0.52-0.88; medians 7.7 v. 3.2 months). ORR was higher in the DT+CT arm, 28% v. 14%, (odds ratio 2.1, p=0.001). Preplanned subgroup analysis demonstrated no significant differences in treatment outcomes by plasma TMB (<20 v. ≥20 mut/Mb, Guardant OMNI), age, sex, or smoking status. There was a trend to improved OS with DT+CT in the subgroup with PD-L1 TPS≥50%, (HR 0.64, 95% CI 0.40-1.04, p=0.07). Plasma TMB<20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95% 1.3-3.1). Toxicity was greater in the DT+CT arm, with grade≥3 adverse events in 82% v. 70%, (p=0.02), most commonly dyspnea, nausea and cough. The incidence of immune-related adverse events was similar between arms (colitis 11%, pneumonitis 6%, endocrinopathy 21%). Grade 5 events occurred in 2.7%, (5 with DT+CT, 3 with DT). Conclusions: The addition of CT to first-line DT did not improve OS in advanced NSCLC. CT+DT improved ORR and PFS, and was associated with greater toxicity. No differential effects were seen by PD-L1 TPS nor bTMB. These data suggest that adding chemotherapy to ICI may be beneficial in those with PD-L1 TPS >=50%, and warrant further analysis in independent datasets. Clinical trial information: NCT03057106 .
5551 Background: Genomic characterization of mCRPC has identified commonly occurring alterations but also recurrently mutated genes at much lower frequencies. To efficiently evaluate anti-tumor activity of novel targeted therapies in mCRPC patients (pts) we initiated an umbrella trial using circulating tumour DNA (ctDNA) to enrich accrual for cancers with alterations that may predict response. Methods: mCRPC pts that have progressed after treatment with a next generation AR-pathway inhibitor (ARPI) were enrolled to this multi-center, multi-arm, 2-stage phase II trial. Plasma cell-free DNA was subjected to targeted sequencing and pts allocated to a treatment arm by a Tumor Board (TB) based on a priori criteria (biomarker positive, BM+) or by randomization if biomarker negative (BM-). Primary objective was to determine the clinical benefit rate (CBR: PSA decline ≥50% (PSA50), CR/PR, or stable disease ≥12 weeks). We report on 1st-stage activity of arms evaluating inhibitors of CDK4/6 (palbociclib), WEE1 kinase (adavosertib), cMET (savolitinib) and the AR inhibitor darolutamide. Additional planned arms include inhibitors of AKT (ipatasertib), Polo-like Kinase 4 (CFI-400945), immune checkpoints (durvalumab, tremelimumab) and carboplatin. Results: 250 pts were screened from two sequential trials over 29 months at 11 centers. Median time from blood draw to TB decision was 35 days. 169 pts (68%) had detectable ctDNA (≥1%) with a mean ctDNA fraction of 24% (range 1-95%). Commonly detected genomic alterations involved AR (49% gain, 24% mutation), TP53 (49%), PTEN/PI3K pathway (35%), DNA repair (23%: mismatch repair (5%), BRCA2 (8%), ATM (3%), CDK12 (5%), other (2%)) and CTNNB1/APC (14%). To date, 46 BM+ pts and 37 BM- patients were enrolled: median age 70 years (53-88), 100% had prior ARPI, 45% had prior docetaxel, 17% with visceral metastases. Accrual and CBR are presented in table. Adverse events were as expected. Conclusions: Prospective centralized screening of ctDNA to stratify mCRPC pts into a precision oncology trial is feasible. Activity was seen in 4 of 7 evaluable cohorts with darolutamide and adavosertib, meeting the threshold for expansion of these arms. Clinical trial information: NCT03385655, NCT02905318 . [Table: see text]
Aim: To evaluate overall survival in advanced cancer patients who achieved complete response (CR) with immune checkpoint inhibitor (ICI) therapy. Methods: This retrospective study included patients with advanced unresectable or metastatic cancer who received at least one cycle of palliative-intent ICI. Best overall response was used to define response groups. Results: 21 (7%) of 322 patients achieved CR. Multivariate analysis demonstrated that CR was independently associated with better overall survival compared with disease progression (hazard ratio: 0.012; 95% CI: 0.002–0.090) and stable disease (hazard ratio: 0.063; 95% CI: 0.009–0.464) as well as a nonsignificant trend toward better overall survival compared with partial response (hazard ratio: 0.169; 95% CI: 0.023–1.252) regardless of cancer type, ICI regimen or ICI line. Conclusion: Patients who achieved CR had longer survival compared with patients who did not achieve CR.
9067 Background: Bone metastasis (BM) occurs in about 40% of patients with metastatic lung cancer. Recently, BM was associated with decreased OS to nivolumab in previously-treated NSCLC (Landi L et al, P1.01.53, 19th WCLC, 2018). CCTG BR.34 (NCT03057106) was an open-label, randomized phase II clinical trial that randomized 301 patients with treatment-naïve, high-risk, stage IVA/B NSCLC without sensitizing EGFR or ALK alterations (1:1) to durvalumab plus tremelimumab with or without platinum doublet chemotherapy. First, 109 patients accrued with stage IVB, or selected IVA disease. Then 192 patients accrued with any stage IVA/B disease. In CCTG BR.34, median OS was not significantly different: 16.6 mo in the chemotherapy plus immunotherapy (C+IO) arm, vs 14.1 mo in the IO alone arm (HR 0.88, p = 0.46) (Leighl NB et al, J Thor Oncol, 2021). However, in BR.34 PFS was significantly longer in the C+IO arm (7.7 mo) compared to the IO alone arm (3.2 mo) (HR 0.67, 95% CI, 0.52 0.88). Here we analyzed the effect of BM on outcomes in BR.34. Methods: The 301 patients in the trial were characterized by the presence of BM at study entry (129-yes, 172-no). BM effect was evaluated on trial outcomes (OS, PFS, and ORR) using Cox/logistic regression analysis. Multivariable analysis was performed adjusting for the clinical and molecular covariates available. Results: In univariate analysis of the entire study population, median OS was significantly shorter for patients with BM vs those without BM (10. 9 vs 18.7 mos, HR 1.68, p = 0.001), as was median PFS (3.4 vs 7.2 mos, HR 1.82, p < 0.0001), and lower ORR (29.5% vs 45.9%, OR 0.52, p = 0.003), respectively. There was no evidence of differential association of BM with treatment arms for OS (p = 0.23), PFS (p = 0.84), and ORR (p = 0.25, Breslow-Day test). In multivariate analysis (MVA), BM remained significantly associated with worse OS (HR 1.44, p = 0.026), PFS (HR 1.69, p < 0.0001), and ORR (OR 0.52, p = 0.01). In MVA for OS: TMB, histology type, race, and ECOG were also significant; but age, smoking history, and PD-L1 IHC status were not significant. Conclusions: In CCTG BR.34 the presence of BM at trial entry was associated with significantly shorter OS, PFS, and lower ORR. BM is therefore a significant adverse prognostic factor in high-risk, stage IVA/B NSCLC treated with durvalumab and tremilimumab (with or without platinum doublet chemotherapy). If confirmed in a larger phase III trial, BM should be considered as an important new stratification factor in all clinical trials of immune checkpoint inhibitor (ICI) therapy. We and others have reported that molecules arising in the bone microenvironment (e.g: IL-8, PTHrP, TGF-b, sclerostin, and activin A) cause immunosuppression in cancer, and future trials should evaluate the addition of targeted therapies against these factors in combination with the ICIs in patients with BM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.