Abstract CT011: NeoCOAST: open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients (pts) with resectable, early-stage non-small-cell lung cancer (NSCLC)

Abstract

Background: Neoadjuvant anti-PD-(L)1 therapy may offer clinical benefit in resectable, early-stage NSCLC. NeoCOAST (NCT03794544) is a global, randomized phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) durvalumab (D) alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Methods: Pts with previously untreated, cytologically/histologically documented, resectable, Stage I [>2 cm]-IIIA NSCLC and ECOG PS 0-1 were randomized 1:1:1:1 (stratified by lymph node involvement) to receive D 1500 mg IV alone Q4W or combined with O 3000 mg IV Q2W, M 750 mg IV Q2W, or Da 200 mg IV QW, for one 28-day cycle, followed by surgery. Da monotherapy was also given on days 1, 3 and 5 of the week prior to combination treatment. The primary endpoint was investigator-assessed major pathological response (MPR; ≤10% residual viable tumor cells at tumor site and nodes, at surgery). Secondary endpoints were pathological complete response (pCR; no viable tumor cells), safety and tolerability, feasibility of surgery, PK and immunogenicity. Exploratory endpoints included tumor and microbiome biomarkers and blood mRNA signatures. Results: From March 2019 to Sept 2020, 84 pts were randomized and 83 received D (n=26), D+O (n=21), D+M (n=20), or D+Da (n=16). MPR occurred in 11.1% (95% CI, 2.4-29.2), 19.0% (95% CI, 5.4-41.9), 30.0% (95% CI, 11.9-54.3), and 31.3% (95% CI, 11.0-58.7%), respectively. pCR occurred in 3.7% (95% CI, 0.1-19.0), 9.5% (95% CI, 1.2-30.4), 10.0% (95% CI, 1.2-31.7%) and 12.5% (95% CI, 1.6-38.3), respectively. Rates of treatment-related AEs were 34.6% with D, 57.1% with D+O, 50.0% with D+M, and 43.8% with D+Da (grade ≥3 in 0%, 4.8%, 0% and 6.3%, respectively). Most pts (76/83; 91.6%) completed surgery with no significant delay; of the 7 pts unable to, 5 had progressive or stage IV disease. Across all arms, MPR was more common in pts with baseline tumor PD-L1 expression ≥1% vs those with <1%. With D, CD73 expression was correlated with greater residual viable tumor cells at surgery; however, with D+O, high CD73 (≥10% tumor cells) was associated with reduced viable tumor cells. Transcriptome analysis of post-treatment and baseline blood samples showed upregulation of genes involved in B cell activation and antigen presentation in pts with MPR in the D+O arm, and upregulation of genes associated with Tregs in pts with MPR in the D+M arm. Conclusions: One cycle of D + O, M or Da improved MPR and pCR rates vs D alone, with no new safety signals. Responses were associated with baseline tumor PD-L1 and CD73 expression levels. Pts with MPR receiving D+O or D+M had peripheral transcriptomic signatures related to immune cell function. These data warrant further investigation of these agents in resectable NSCLC. Citation Format: Tina Cascone, Rosario García-Campelo, Jonathan Spicer, Walter Weder, Davey Daniel, David Spigel, Maen Hussein, Julien Mazieres, Julio Oliveira, Edwin Yau, Alexander Spira, Raymond Mager, Oday Hamid, Lin-Yang Cheng, Ying Zheng, Jorge Blando, Lara McGrath, Italia Grenga, Yee Soo-Hoo, Rakesh Kumar, Patrick Forde. NeoCOAST: open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients (pts) with resectable, early-stage non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT011.

Progress on neoadjuvant immunotherapy in resectable non-small cell lung cancer and potential biomarkers

“…In the further analysis of the other primary endpoint (31), event-free survival (EFS, defined as the length of time from randomization to any disease progression precluding surgery, disease progression or recurrence after surgery, or death due to any cause), the superior efficacy of combined therapy was proved again. The median EFS of combined therapy reached 31.6 months (95%CI, 30.2-NR), which reflected a 10.8 months longer event-free survival as In AACR 2022, Cascone, T., et al reported results from the phase 2, randomized multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients with resectable NSCLC(NeoCOAST) (32). Patients with stage I-IIIA NSCLC were given durvalumab alone or combined with the anti-CD73 mAb oleclumab, the anti-NKG2A mAb monalizumab, or the anti-STAT3 antisense oligonucleotide danvatirsen as neoadjuvant therapy for one cycle followed by surgery.…”

Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors

“…Oleclumab showed to improve PFS and to have a manageable safety profile [ 190 ]. In a phase II study, NeoCOAST durvalumab alone or combined with oleclumab, monalizumab or danvatirsen (the anti-STAT3 antisense oligonucleotide) has been evaluated as neoadjuvant therapy in patients with previously untreated, resectable, stage I-IIIA NSCLC [ 191 ]. One cycle of durvalumab in combination with other agents improved pCR and major pathological response rates versus durvalumab alone whit the same safety proflile.…”

Moving Immune Checkpoint Inhibitors to Early Non-Small Cell Lung Cancer: A Narrative Review

“…The study was not formally powered to compare arms, but MPR investigator-assessed rates ranged from 19% (oleclumab arm) to 31.3% (danvatirsen group). Whole RNA sequencing was performed on paired baseline and post-surgery tissue, demonstrating a greater increase of expression of genes associated with NK and CD8 T cells, cytotoxicity, tertiary lymphoid structures and lymphocyte recruitment with durva+mona or durva+ole than with durvalumab alone [ 61 ]. Building on these results, a phase III follow-up randomized clinical trial, NeoCOAST-2, is currently enrolling [ 62 ].…”

“…In the LCMC3 study, among 16 EGFR/ALK positive tumors at resection, no one demonstrated a radiographical response or MPR [ 58 ]. Conversely, in NeoCOAST, among patients with MPR, two had EGFR mutations (both in durva + ole arm) [ 61 ].…”