Long-term outcomes with nivolumab (Nivo) vs docetaxel (Doc) in patients (Pts) with advanced (Adv) NSCLC: CheckMate 017 and CheckMate 057 2-y update

Steins, Martin; Horn, Leora; Ready, Neal; Felip, E.; Borghaei, Hossein; Spigel, David R.; Arrieta, Óscar; Antonia, S.; Fayette, Jérôme; Rizvi, Naiyer A.; Crinò, L.; Reck, Martin; Eberhardt, W; Hellmann, Matthew D.; Geese, William J.; Li, A.; Healey, Diane; Brahmer, Julie R.; Paz‐Ares, Luis

doi:10.1093/annonc/mdw383.15

Cited by 20 publications

(20 citation statements)

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“…An OS benefit with nivolumab has been demonstrated regardless of tumor PD-L1 expression level in previously treated squamous NSCLC (9), whereas the magnitude of the OS benefit appeared to be greater with increasing PD-L1 expression in previously treated nonsquamous NSCLC (10,29). In our analyses, PD-L1 expression was significantly associated with OS in patients with nonsquamous but not squamous NSCLC, which is consistent with observations in the clinical trials (9,10).…”

Section: Discussionsupporting

confidence: 89%

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Yan

Wang

Bajaj

et al. 2017

Clinical Cancer Research

109

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Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n ¼ 293) or nonsquamous (n ¼ 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between timeaveraged nivolumab concentration after the first dose (C avg1 ) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab C avg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC.

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Section: Discussionsupporting

confidence: 89%

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Yan

Wang

Bajaj

et al. 2017

Clinical Cancer Research

109

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“…It has additionally been implicated as a mechanism of resistance to immunotherapies including T-cell based therapies and vaccination in patients with advanced melanoma (29,40). Recently, a case of advanced melanoma with acquired resistance to the anti-PD-1 antibody, pembrolizumab, presumably mediated by B2M deficiency was reported (12). This patient’s resistant tumor harbored a homozygous B2M truncating mutation, with loss of cell surface HLA class I expression.…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 axis antagonist antibodies in non-small cell lung cancer (NSCLC) can induce durable anti-tumor responses (median duration of response, 12 to 25 months) (5–12), with some responses lasting well beyond 5 years (13). The longest follow up study of NSCLC patients treated with such therapy to date showed an unprecedented 16 percent 5-year survival rate among patients with pre-treated advanced NSCLC (13).…”

Section: Introductionmentioning

confidence: 99%

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

et al. 2017

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Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock-out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

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“…The median duration of response in non‐squamous NSCLC patients treated with nivolumab was 17.2 months (95% CI; 8.4‐not estimated (NE)) compared with 5.6 months (95% CI; 4.4–6.9) for those treated with docetaxel . This suggests that the effect of nivolumab tends to last longer once the patient achieves SD or greater .…”

Section: Discussionmentioning

confidence: 99%

“Lazarus response” of nivolumab in a frail patient with non-small-cell lung cancer

Takeda¹,

Takeuchi²,

Nishimi³

et al. 2017

Respirology Case Reports

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Lung cancer has aggressive behaviour which often progresses rapidly with disseminated disease and leads to poor performance status (PS) in patients. Because cytotoxic chemotherapy is not recommended under these conditions, there are currently no alternative therapeutic options other than providing supportive care. Immune checkpoint inhibitors have been developed, but their efficacy and tolerability have not been fully investigated in patients with poor PS. A 72-year-old male patient with lung adenocarcinoma harbouring no EGFR-sensitizing mutation or ALK translocation was receiving second-line chemotherapy with S-1 monotherapy when he complained of worsening dyspnea. Chest computed tomography (CT) demonstrated disease progression at the primary site that was accompanied by bilateral pulmonary lymphangitic carcinomatosis, which was the cause for respiratory failure. Oxygen administration at 10 L/min was required due to the rapid progression of the tumour that resulted in poor PS. A retrospective study was conducted to assess the upregulation of programmed death ligand 1 (PD-L1) using anti-PD-L1 22C3 mouse monoclonal primary antibody and found that the PD-L1 expression was 50-60% (i.e. tumour proportion score ≥50%). Since cytotoxic chemotherapy could not be considered due to a poor PS of 4, nivolumab was cautiously administered. After the introduction of nivolumab, ground glass opacities, and consolidations on chest CT temporarily deteriorated on day 4 without any other clinical signs and symptoms. The reevaluation on day 10 demonstrated significant improvements on chest X-ray. Then the patient was subsequently diagnosed with pseudoprogression. Thereafter, both the respiratory status and the PS improved gradually. The PS recovered to baseline conditions with oxygen administration at 1 L/min after four cycles of treatment. The patient currently remains at a PS of 1 and is progression-free for eight months after the introduction of nivolumab.

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Long-term outcomes with nivolumab (Nivo) vs docetaxel (Doc) in patients (Pts) with advanced (Adv) NSCLC: CheckMate 017 and CheckMate 057 2-y update

Cited by 20 publications

References 0 publications

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

“Lazarus response” of nivolumab in a frail patient with non-small-cell lung cancer

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