Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

Antonia, Scott; López-Martín, José A.; Bendell, Johanna C.; Ott, Patrick A.; Taylor, Matthew H.; Eder, Joseph P.; Jäger, Dirk; Pietanza, M. Catherine; Le, Dung T.; Braud, Filippo de; Morse, Michael A.; Ascierto, Paolo A.; Horn, Leora; Amin, Asim; Pillai, Rathi N.; Evans, Jeffry; Chau, Ian; Bono, Petri; Atmaca, Akin; Sharma, Padmanee; Harbison, Christopher; Lin, Chen Sheng; Christensen, Olaf; Calvo, Emiliano

doi:10.1016/s1470-2045(16)30098-5

Cited by 1,127 publications

(1,023 citation statements)

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“…However, the majority of patients either do not respond upfront or eventually progress. Combination immunotherapies with agents such as CTLA-4 inhibitors may enhance efficacy and responses but also substantially increase toxicity, as reported in patients with melanoma or lung cancer (22,23). Despite the successes of PD-1 checkpoint blockade across various malignancies, an urgent need still exists to improve outcomes and survival for patients with advanced solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Tolcher

Sznol

Hu‐Lieskovan

et al. 2017

Clinical Cancer Research

198

134

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Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8þ T cells was observed in responders versus nonresponders.Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.

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Section: Discussionmentioning

confidence: 99%

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Tolcher

Sznol

Hu‐Lieskovan

et al. 2017

Clinical Cancer Research

198

134

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“…Immune checkpoint receptors such as PD-1 and CTLA-4, whose blockade through mAbs recently showed significant response rates in otherwise pretreated patients, 11,30 are upregulated on activated T cells. In the tumor microenvironment, T cells expressing PD-1 have been identified as clonal expansion of tumor reactive T cell populations, thus representing functionally important components in order to eliminate tumor cells.…”

Section: Discussionmentioning

confidence: 99%

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

et al. 2018

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The role of T cell receptor (TCR) signaling for adaptive immune responses is essential. The ability to respond to a broad spectrum of tumor antigens requires an adaptive selection of various TCR. So far, little is known about the role of TCR richness and clonality in the cellular immune response to head and neck cancer (HNC), though the Endothelial Growth Factor Receptor (EGFR)-specific CD8+ T cell response can be enhanced by cetuximab therapy. Therefore, we investigated differences in TCR sequences between human papillomavirus (HPV)+ and HPV− HNC patients, as well as differences in TCR sequence characteristics between T cells of peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL). Additionally, we were able to investigate the TCR richness and clonality in samples pre- and post- treatment in a prospective clinical trial of neoadjuvant cetuximab. Interestingly, HPV+ and HPV− HNSCC did not significantly differ in the extent of TCR clonality and richness in PBMC or TIL. However, neoadjuvant cetuximab treatment increased the number of unique TCR sequences in PBMC (p = 0.0003), which was more prominent in the clinical responder patients compared to non-responders (p = 0.04). A trend toward TCR gene focusing was observed in TIL (p = 0.1) post-treatment. Thus, an increase in richness of TCR sequences in the periphery with a focusing at the tumor site is associated with an improved treatment response, suggesting an influence of peripheral quantity and intratumoral quality on adaptive immunity in cetuximab treated patients.

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“…The first report of the smallcell lung cancer cohort included 216 patients allocated in three different schedules: nivolumab alone or in combination with ipilimumab at two different doses. Anti-tumour activity in small-cell lung cancer patients was seen in all schedules (15). Confirmed responses were observed in 10% (95% CI: 5-18) of patients with nivolumab 3 mg/kg, 23% (13-36%) with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (9-31%) with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.…”

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confidence: 85%

“…Notably in the CheckMate 032 trial an essentially equal likelihood of responses was observed in PD-L1 negative and PD-L1 positive small-cell lung cancer tumors, not only in the nivolumab cohort but also in the combination cohort, suggesting that PD-L1 does not enrich for response in small-cell lung cancer (15). Whether PD-L1 expression is of any predictive utility in small-cell lung cancer must await analysis in a larger population.…”

mentioning

confidence: 99%

“…Reported PD-L1 expression in retrospective studies in small-cell lung cancer varies widely, from a few percentage points to over 70% (18,19). In the Keynote-028 trial, a reported 31.7% of small-cell lung cancer patients tested for PD-L1 expression were positive, whereas only 17% of the analyzed patients in the CheckMate 032 had a PD-L1 expression ≥1% (15,17).…”

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confidence: 99%

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Small-cell lung cancer in the era of immunotherapy

Majem

Rudin

2017

Transl. Lung Cancer Res.

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Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

Abstract: There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/118215/

Cited by 1,127 publications

References 35 publications

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

Small-cell lung cancer in the era of immunotherapy

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