Herbst, R.S. (Roy S.)
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- Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small- cell lung cancer(BMJ, 2022) Martínez-Morilla, S. (Sandra); Zugazagoitia, J. (Jon); Moutafi, M.K. (Myrto K.); Molero, M. (Magdalena); Rimm, D.L. (David L.); Adradas, V. (Vera); Castro-Labrador, L. (Laura); Montuenga-Badia, L.M. (Luis M.); Vathiotis, I.A. (Ioannis A.); Orive-Mauleón, D. (Daniel); Gavrielatou, N. (Niki); Herbst, R.S. (Roy S.); Valencia, K. (Karmele); Paz-Ares, L. (Luis); Ruiz-de-Garibay, G. (Gorka); Baena, J. (Javier); Calvo-González, A. (Alfonso); Schalper, K.A. (Kurt A.); Ponce-Aix, S. (S.)Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC.
- PD-1/PD-L1 blockers in NSCLC brain metastases: Challenging paradigms and clinical practice(American Association for Cancer Research, 2020) Gil-Bazo, I. (Ignacio); Lu, B.Y. (Benjamin Y.); Eguren-Santamaría, I. (Iñaki); Goldberg, S. (S.); Kluger, H. (Harriet); Herbst, R.S. (Roy S.); Idoate, M.A. (Miguel Ángel); Corral, J. (Jesús); Schalper, K.A. (Kurt A.); Fernandez-Sanmamed, M. (Miguel)Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). However, most pivotal phase III trials systematically excluded patients with active brain metastases, precluding the generalization of the results. Although theoretically restricted from crossing the blood-brain barrier, the novel pharmacokinetic/pharmacodynamic profiles of anti-PD-1/PD-L1 drugs have prompted studies to evaluate their activity in patients with NSCLC with active central nervous system (CNS) involvement. Encouraging results have suggested that ICI could be active in the CNS in selected patients with driver-negative advanced NSCLC with high PD-L1 expression and low CNS disease burden. Single-agent CNS response rates around 30% have been reported. Beyond this particular setting, anti-PD-1/PD-L1 antibodies have been evaluated in patients receiving local therapy for brain metastases (BM), addressing concerns about potential neurologic toxicity risks associated with radiotherapy, more specifically, radionecrosis (RN). Accordingly, a variety of clinical and imaging strategies are being appropriately developed to evaluate tumor response and to rule out pseudoprogression or radionecrosis. Our purpose is to critically summarize the advances regarding the role of systemic anti-PD-1/PD-L1 antibodies for the treatment of NSCLC BM. Data were collected from the PubMed database, reference lists, and abstracts from the latest scientific meetings. Recent reports suggest anti-PD-1/PD-L1 agents are active in a subset of patients with NSCLC with BM showing acceptable toxicity. These advances are expected to change soon the management of these patients but additional research is required to address concerns regarding radionecrosis and the appropriate sequencing of local and systemic therapy combinations.
- A burned-out CD8(+) T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy(2021) Wang, J. (Jun); Villaroel-Espíndola, F. (Franz); Han, X. (Xue); Nie, X. (Xinxin); Zhang, Y. (Yu); Desai, S. (Shruti); Badri, T. (Ti); Kim, T.K. (Tae Kon); Melero, I. (Ignacio); Zhao, D. (Dejian); Vesely, M.D. (Matthew D.); Ji, L. (Lan); Herbst, R.S. (Roy S.); Kim, A.W. (Anthony W.); Sun, J. (Jingwei); Schalper, K.A. (Kurt A.); Cheng, X. (Xiaoxiao); Fernandez-Sanmamed, M. (Miguel); Quinlan, E. (Edward); Zhang, T. (Tianxiang); Nassar, A.F. (Ala F.); Chen, L. (Lieping)Specific mechanisms by which tumor-infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 patients with resectable and 35 patients with advanced non-small cell lung cancer (NSCLC). We identified a burned-out CD8(+) TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME) but not in adjacent nontumoral tissues. Ebo showed the highest expression of proliferation and activation markers but produced the lowest amount of IFN gamma and were the most apoptotic CD8(+) TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in patients with NSCLC. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance. SIGNIFICANCE: We identified a highly proliferative, overactivated, and apoptotic dysfunctional CD8(+) tumor-infiltrating subpopulation that is functionally distinct from previously described exhausted T cells. This population is expanded in lung cancer tissues in a PD-1/B7-H1-dependent manner, and its abundance is associated with resistance to cancer immunotherapy, thus becoming a potential tissue biomarker.
- Long-term follow-up in the KEYNOTE-010 study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who completed 2 years of pembro and pts who received a second course of pembro(Elsevier, 2018) Dubos-Arvis, C. (C.); Perez-Gracia, J.L. (Jose Luis); Kim, D.W; Baas, P. (P.); Lubiniecki, G.M (G. M.); Novello, S. (S.); Samkari, A. (A.); Chul-Cho, B. (B.); Su, W.C. (W. C.); Gubens, M.A. (M. A.); Han, J.Y. (J. Y.); Herbst, R.S. (Roy S.); Garon, E.B. (E. B.); Szalai, Z. (Z.); Majem-Tarruella, M. (Margarita); Ceresoli, G.L. (G. L.); Jensen, E.H. (E. H.); Forster, M. (M.); Monnet, I. (I.)In the global, open-label, phase 2/3 study KEYNOTE-010, pembro 10 mg/kg or 2 mg/kg Q3W improved OS vs docetaxel in pts with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1% (coprimary analyses) at median follow-up of 13.1 mo. We present long-term results overall, in pts who completed 35 cycles (∼2 y) of pembro, and in pts who received a second course of pembro.
- Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial(Elsevier BV, 2019) Fidler, M.J. (M. J.); Emancipator, K. (K.); Dubos-Arvis, C. (C.); Garrido, M. (M.); Perez-Gracia, J.L. (Jose Luis); Felip, E. (Enriqueta); Kim, D.W; Kim, J.H. (J. H.); Castro-Jr, G. (G.) de; Baas, P. (P.); Lubiniecki, G.M (G. M.); Samkari, A. (A.); Han, J.Y. (J. Y.); Surmont, V. (V.); Herbst, R.S. (Roy S.); Garon, E.B. (E. B.); Ahn, M.J. (M. J.); Molina, J.R. (J. R.); Majem-Tarruella, M. (Margarita); Jensen, E.H. (E. H.); Shentu, Y. (Y.)Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.