Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study

Felip, Enriqueta; Braud, Filippo G. De; Maur, M; Loong, Herbert H.; Shaw, Alice T.; Vansteenkiste, Johan; John, Thomas; Liu, Geoffrey; Lolkema, Martijn P.; Selvaggi, Giovanni; Giannone, Vanessa; Cazorla, Pilar; Baum, Jason; Balbin, O. Alejandro; Wang, Luojun Victor; Lau, Yvonne; Scott, Jeffrey W.; Tan, Daniel Shao-Weng

doi:10.1016/j.jtho.2019.10.006

Cited by 60 publications

(38 citation statements)

References 21 publications

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“…Our preclinical studies showed that when CER is used in combination with anti‐PD‐L1 therapy, tumor cells have a synergistic killing effect, which highlights that reactivation of ERK signals is a hallmark feature of combination therapy. More importantly, a recent open‐label, phase IB, multicenter, dose‐escalation and expansion study provides proof‐of‐concept that both ALKi‐naïve and ALKi‐pretreated patients benefit from the combined strategy of CER plus nivolumab with an ORR range of 25%‐80%, 43 which further confirmed our present in vitro and in vivo results.…”

Section: Discussionsupporting

confidence: 86%

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

et al. 2020

Cancer Science

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Both ceritinib (CER) and programmed cell death (PD)‐1/PD ligand‐1 (PD‐L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)‐rearranged non‐small‐cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD‐1/PD‐L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD‐L1 inhibitor in ALK‐rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD‐L1 inhibitor in vitro by quantitative RT‐PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4‐ALK‐WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD‐L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD‐L1 and phospho‐ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD‐L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD‐L1 inhibitor in combination were significantly smaller than those treated with CER or PD‐L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD‐L1 inhibitor, and CER plus PD‐L1 groups, respectively. Ceritinib could synergize with PD‐1/PD‐L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD‐L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD‐L1 blockade as combination therapy in clinical therapeutic practice.

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Section: Discussionsupporting

confidence: 86%

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

et al. 2020

Cancer Science

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“…Currently, the evidence is still limited for clinicians to apply immunotherapy to ALK-positive patients. Combined ALK inhibitor(s) and immunotherapy may lead to a higher toxicity 33 . In addition to prognosis estimation, biomarker assessment and patient sorting may provide an opportunity for subsequent research.…”

Section: Discussionmentioning

confidence: 99%

ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients

Chang

Yang

Chen

et al. 2020

Sci Rep

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It remains unclear how programmed death-ligand 1 (PD-L1) expression interacts with anaplastic lymphoma kinase (ALK) mutation, its variants, and the outcome of treatment. One hundred and twenty four out of 1255 patients (9.9%) were deemed ALK-positive by the Ventana IHC assay. PD-L1 status and ALK variants were available in 100 and 59 patients, respectively. PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rate was 50% and 16%, respectively. A total of 64 variant types were detected in 59 patients. V1 (32.8%) and V3a/b (28.1%) were the most common variants. There was no significant association between ALK variants and the PD-L1 expression. The presence of V3a/b subtype independently predicted a worse overall survival in patients receiving ALK inhibitor(s) (aHR 5.10 [95% CI 1.22–21.25], P = 0.025) and platinum plus pemetrexed (aHR 9.62 [95% CI 1.90–48.80], P = 0.006). While incorporating ALK variants and PD-L1 expression together, patients with non-V3a/b/positive PD-L1 showed a trend towards longer OS. In conclusion, ALK-positive NSCLC patients possess a high PD-L1 expression rate. Although there was no significant association between PD-L1 expression and ALK variants, the outcome of ALK-positive patients could be sorted by these two biomarkers.

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“… 14 More recently, a combination of ceritinib plus nivolumab was shown to have activity, particularly in patients with high PD-L1 expression. 15 However, significant hepatotoxicities, as represented by increased ALT level, were reported in combination trials consisting of ALK TKI and ICIs, 15 16 and the mechanisms underlying hepatotoxicities remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer

Pyo

Lim

Park

et al. 2020

J Immunother Cancer

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BackgroundEML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) have not proved efficacy in ALK-positive non-small cell lung cancer so far. In this study, we performed a mouse clinical trial using EML4-ALK transgenic mice model to comprehensively investigate immunomodulatory effects of ALK TKI and to investigate the mechanisms of resistance to ICIs.MethodsEML4-ALK transgenic mice were randomized to three treatment arms (arm A: antiprogrammed death cell protein-1 (PD-1), arm B: ceritinib, arm C: anti-PD-1 and ceritinib), and tumor response was evaluated using MRI. Progression-free survival and overall survival were measured to compare the efficacy. Flow cytometry, multispectral imaging, whole exome sequencing and RNA sequencing were performed from tumors obtained before and after drug resistance.ResultsMouse clinical trial revealed that anti-PD-1 therapy was ineffective, and the efficacy of ceritinib and anti-PD-1 combination was not more effective than ceritinib alone in the first line. Dynamic changes in immune cells and cytokines were observed following each treatment, while changes in T lymphocytes were not prominent. A closer look at the tumor immune microenvironment before and after ceritinib resistance revealed increased regulatory T cells and programmed death-ligand 1 (PD-L1)-expressing cells both in the tumor and the stroma. Despite the increase of PD-L1 expression, these findings were not accompanied by increased effector T cells which mediate antitumor immune responses.ConclusionsALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors.

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Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study

Cited by 60 publications

References 21 publications

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients

Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer

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