Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial

Herbst, Roy S.; Baas, Paul; Kim, Dong Wan; Felip, Enriqueta; Pérez-Gracia, José Luis; Han, Ji Youn; Molina, Julian R.; Kim, Joo Hang; Arvis, Catherine Dubos; Ahn, Myung Ju; Majem, Margarita; Fidler, Mary J.; Castro, Gilberto de; Garrido, Marcelo; Lubiniecki, Gregory M.; Shentu, Yue; Im, Ellie; Dolled‐Filhart, Marisa; Garon, Edward B.

doi:10.1016/s0140-6736(15)01281-7

Cited by 5,451 publications

(4,813 citation statements)

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“…Immunotherapy using antibodies targeting checkpoint proteins has become of increasing interest and a number of clinical trials using these antibodies for several different cancer types have shown clinical responses 22, 23, 24, 25, 26, 27, 28. However, studies with animal models and cancer patients have also shown that combining antibody blockade of the PD‐1/PD‐L1 axis with other forms of immunotherapy can lead to more meaningful clinical responses 32, 33, 34, 35.…”

Section: Discussionmentioning

confidence: 99%

“…One consistency is demonstrations that blocking PD‐1 increased progression‐free survival of patients with melanoma, although the rates of complete responses were low 23. Similarly, blocking PD‐1 in patients with non‐small‐cell lung cancer prolonged progression‐free survival, but cancer nevertheless progressed in almost all patients 25. The most direct consistency with the present study's demonstration of a transient immunological response to PD‐1 blockade is demonstration of acquired resistance to PD‐1 antibody treatment in melanoma patients 43.…”

Section: Discussionmentioning

confidence: 99%

“…In a trial involving recurrent or metastatic HNSCC patients for whom there were few treatment options, pembrolizumab was manageably tolerated and demonstrated clinical effectiveness, particularly in subjects with PD‐L1‐positive tumors 24. Similarly, pembrolizumab treatment of patients with PD‐L1‐positive advanced non‐small‐cell lung cancer prolonged their overall survival 25. Using a different PD‐1 blockade antibody, nivolumab, clinical efficacy was shown for patients with metastatic renal cell carcinoma and for patients with ovarian cancer 26, 27.…”

Section: Introductionmentioning

confidence: 99%

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Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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“…The PD-1 (programmed cell death-1) inhibitors nivolumab and pembrolizumab as well as the PD-L1 (programmed cell death ligand-1) inhibitor atezolizumab are all approved for the treatment of advanced NSCLC after large trials demonstrated their superiority to docetaxel chemotherapy in patients that have progressed on standard platinum-based doublet chemotherapy [51–54]. Pembrolizumab has also been approved as initial therapy for patients with metastatic NSCLC with PDL1 expression ≥50% as evaluated by IHC [55] or in conjunction with carboplatin and pemetrexed as first-line therapy for all non-squamous histologies irrespective of PD-L1 expression [58].…”

Section: Post-alk Inhibitor Therapymentioning

confidence: 99%

“…Lack of activity of PD-1/PD-L1-directed agents has also been observed in patients who are never smokers and in patients with EGFR mutation-positive NSCLC [51, 52, 61]. It has been shown that NSCLC patients with tumors that have a high mutational burden have a greater probability of benefit from checkpoint inhibition [62].…”

Section: Post-alk Inhibitor Therapymentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors

2018

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Key Points Question Does the treatment effect size differ between overall survival and progression-free survival for PD-1 (programmed cell death 1) inhibitors used in patients with advanced solid tumors, and are overall survival and progression-free survival correlated? Findings This meta-analysis of 12 randomized clinical trials found no significant correlation between overall survival and progression-free survival in terms of medians and gains in medians, but their hazard ratios were significantly correlated. The protective effects of treatment were greater for overall survival than for progression-free survival. Meaning Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, overall survival should remain the gold standard end point for trials of PD-1 inhibitors.

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Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial

Cited by 5,451 publications

References 31 publications

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors

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