Pembrolizumab Plus Chemotherapy in Squamous Non–Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study
Three trial updates confirm what we already know and practice.
COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non–Small-Cell Lung Cancer
Author(s): Roy S. Herbst, MD, PhD1; Margarita Majem, MD, PhD2; Fabrice Barlesi, MD, PhD3; Enric Carcereny, MD4; Quincy Chu, MD5; Isabelle Monnet, MD, PhD6; Alfredo Sanchez-Hernandez, MD7; Shaker Dakhil, MD8; D. Ross Camidge, MD, PhD9; Leanne Winzer, MSc10; Yee Soo-Hoo, MPH11; Zachary A. Cooper, PhD11; Rakesh Kumar, MD, PhD11; John Bothos, PhD11; Charu Aggarwal, MD, MPH12; and Alex Martinez-Marti, MD13
Source: 10.1200/JCO.22.00227 Journal of Clinical Oncology 40, no. 29 (October 10, 2022) 3383-3393
Dr. Maen Hussein's Thoughts
Oleclumab (MEDI9447) is a human IgG1λ mAb that inhibits the function of cluster of differentiation 73 (CD73).8 CD73 is an enzyme found on the surfaces of cancer and immune cells and is involved in conversion of adenosine monophosphate to extracellular adenosine, which has an immunosuppressive effect on the tumor environment.9 CD73 upregulation by tumors has been shown to increase extracellular adenosine production and result in subsequent local immunosuppression in multiple cancers.
Monalizumab (IPH2201) is a first-in-class, humanized, IgG4 mAb that specifically binds to and blocks the inhibitory receptor NKG2A from binding to the major histocompatibility complex E (HLA-E), thereby reducing inhibition of natural killer and CD8+ T cells.14 HLA-E is overexpressed in multiple tumor types and, once bound to NKG2A, triggers inhibitory signals that suppress cytokine secretion and direct cytotoxicity of T lymphocytes and natural killer cells.15 Monalizumab binds specifically and with high affinity to NKG2A, thereby suppressing inhibitory signals and enhancing antitumor immunity.
Both seems to have synergy with PD-1/PDL-1 inhibitors without significant added toxicity.
ABSTRACT
PURPOSE
Durvalumab significantly improves overall survival for patients with unresectable stage III non–smallcell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting.
METHODS
Patients with unresectable stage III non–small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, # 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1).
RESULTS
Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade $ 3 treatmentemergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively.
CONCLUSION
Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.
Author Affiliations
1Yale Cancer Center, New Haven, CT; 2Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 3Gustave Roussy, Villejuif, France; 4Institut Català d’Oncologia, Badalona-Hospital Germans Trias i Pujol, Barcelona, Spain; 5Cross Cancer Institute, Edmonton, AB, Canada; 6Centre Hospitalier Intercommunal de Créteil, Créteil, France; 7Consorcio Hospitalario Provincial de Castellón, Castellón, Spain; 8Cancer Center of Kansas, Wichita, KS; 9University of Colorado Anschutz Medical Campus, Aurora, CO; 10AstraZeneca, Cambridge, United Kingdom; 11AstraZeneca, Gaithersburg, MD; 12Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 13Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Barcelona, SpainRelated Articles
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Confirms what we already know. No real surprises.
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