Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

Antonia, Scott; Villegas, A.; Daniel, Davey B.; Vicente, David; Murakami, Shuji; Hui, Rina; Yokoi, Takashi; Chiappori, Alberto; Lee, Ki Hyeong; Wit, Maike de; Cho, Byoung Chul; Bourhaba, Maryam; Quantin, Xavier; Tokito, Takaaki; Mekhail, Tarek; Planchard, David; Kim, Young‐Chul; Karapetis, Christos Stelios; Hiret, Sandrine; Ostoros, Gyula; Kubota, Keiichi; Gray, Jhanelle E.; Paz‐Ares, Luis; Castro, Javier de; Wadsworth, Catherine; Melillo, Giovanni; Jiang, Haiyi; Huang, Yifan; Dennis, Phillip A.; Özgüroǧlu, Mustafa

doi:10.1056/nejmoa1709937

Cited by 3,439 publications

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“…12,13 ). However, even among such potentially immunogenic cancers, immune checkpoint inhibitors benefit only a relatively small number of patients 7,12,14–18 . As resistance may be due to the activation of alternative checkpoint pathways, additional immune checkpoints targets have become a subject of active research, including the T-cell Immunoglobulin and Mucin-domain- containing molecule 3 (TIM-3) 19 .…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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“…Among 713 lung cancer patients who underwent chemoradiotherapy and randomization, the median progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p < 0.001). The median time to death or distant metastasis was substantially longer with durvalumab than with placebo (23.2 months vs 14.6 months; p < 0.001) [20].…”

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confidence: 89%

“…In this trial, progression-free survival and overall survival were used as primary end points. On September 8, 2017, Antonia and colleagues reported an interim Editorial Cheng, Durm, Hanna, Einhorn & Kong analysis of this Phase III PACIFIC study [20]. Among 713 lung cancer patients who underwent chemoradiotherapy and randomization, the median progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p < 0.001).…”

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confidence: 99%

Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

et al. 2017

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Systemic therapy including platinum-based chemotherapy and targeted therapy has been a mainstay of treatment for the majority of patients with metastatic non-small-cell lung cancer (NSCLC). Recent breakthroughs in immune checkpoint blockade, along with a deeper understanding of tumor immune biology, have led to a paradigm shift in the standard of care for cancer treatment. By activating the immune system to recognize and eliminate cancer, immune checkpoint blockade has the potential to elicit durable responses and augment survival outcomes for a subset of patients [1,2]. In addition, the ability of radiotherapy to induce an immunogenic response and neutralize the immune-suppressive effects of the tumor microenvironment, uniquely positions it as a synergistic tool at the center of emerging multimodal therapies utilizing immune checkpoint blockade [3][4][5][6][7].Immune checkpoint inhibitors of the PD-1/PD-L1 pathway have emerged as a promising new therapeutic strategy [8][9][10][11]. These agents have produced durable clinical responses and antitumor activity in Phase I trials, leading to subsequent randomized Phase II and III trials that demonstrated significant improvements in overall survival when compared with cytotoxic chemotherapy alone [12][13][14][15][16]. These studies have established PD-1/PD-L1 pathway blockade as a powerful new line of therapy for patients with advanced NSCLC following progression after platinum-based therapy [9,11]. Despite unprecedented improvements in clinical outcomes, less than 20% of patients respond to anti-PD-1/PD-L1 agents, necessitating strategies that explore combined treatment modalities in order to extend the benefits of immune checkpoint blockade to a broader patient population. The Phase II KEYNOTE-021 trial (NCT02039674), for example, evaluated the treatment of pembrolizumab in combination with pemetrexed and carboplatin and found significantly prolonged progression-free survival (median 13.0 vs 8.9 months; 6-month survival 92% for both arms) for patients with previously untreated metastatic nonsquamous NSCLC [17]. This trial, as well as the KEYNOTE-024 trial (NCT02142738), has served to bring PD-1 inhibition into the front-line setting for NSCLC [13].Radiation has become known for its abscopal effect in lung cancer. There are many compelling reasons to combine radiotherapy with checkpoint inhibition in the treatment of NSCLC. Radiation affects the immune system in many ways including release of neoantigens, upregulation of PD-L1 on tumor cells, recruitment of T cells to the tumor bed and neutralization of the immune-suppressive effects of the tumor microenvironment. Over 60% of patients with NSCLC require radiotherapy at least once during their course of treatment, and radiotherapy used in combination with immune checkpoint blockade has shown potential in preclinical and early clinical studies [3,6,7,18]. A Phase II trial of consolidation pembrolizumab initiated 1-2 months after concurrent chemoradiation demonstrated safety of such treatment [19]. In fact, in May 2017...

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“…Although not yet approved by the FDA, durvalumab was recently added to the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC as consolidation therapy for patients with unresectable stage III NSCLC who have received two or more cycles of definitive concurrent chemoradiation [70,71].…”

Section: Key Pointsmentioning

confidence: 99%

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

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Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

Abstract: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Cited by 3,439 publications

References 20 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

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