Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Basté, Neus; Bratland, Åse; Roy, Ananya; Zhang, Yayan; Gümüşçü, Burak; Cheng, Jonathan D.; Jin, Fan; Lerzo, Guillermo; Tatangelo, Marcelo; Varela, Mirta; Zarbá, Juan José; Boyer, Michael; Gan, Hui; Gao, Bo; Hughes, Brett; Mallesara, Girish; Rischin, Danny; Taylor, Anne L.; Burian, Martin; Fuereder, Thorsten; Greil, Richard; Barrios, Carlos H.; Castro, Dalvaro Oliveira de; Castro, Gilberto de; Franke, Fábio; Girotto, Gustavo; Lima, Iane Pinto Figueiredo; Nicolau, Ulisses Ribaldo; Pinto, Gustavo Dix Junqueira; Santos, Lucas Vieira dos; Victorino, Ana-Paula; Chua, Neil; Couture, Félix; Gregg, Richard; Hansen, Aaron R.; Hilton, John; McCarthy, Joy; Soulières, Denis; Ascuí, Rodrigo; Gonzalez, Pablo; Villanueva, Luis; Torregroza, Marco; Zambrano, Ángela R.; Holeckova, Petra; Král, Zdeněk; Melichar, Bohuslav; Jana, Prausova; Vošmik, Milan; Andersen, Maria; Gyldenkerne, Niels; Jürgens, Hannes; Putnik, Kadri; Reinikainen, Petri; Gruenwald, Viktor; Laban, Simon; Aravantinos, G.; Boukovinas, Ioannis; Georgoulias, Vassilis; Psyrri, Amanda; Kwong, Dora L.W.; Al-Farhat, Yousuf; Csőszi, Tibor; Erfán, József; Horvai, Geza; Littmann, László; Remenár, Éva; Ruzsa, Ágnes; Judit, Szota; Billan, Salem; Gluck, Iris; Gutfeld, Orit; Popovtzer, Aron; Benasso, Marco; Bui, Simona; Ferrari, Vittorio; Licitra, Lisa; Nolè, Franco; Fujii, Takashi; Fujimoto, Yasushi; Hanai, Nobuhiro; Hara, Hiroki; Matsumoto, Koji; Mitsudo, Kenji; Monden, Nobuya; Nakayama, Masahiro; Okami, Kenji; Oridate, Nobuhiko; Shiga, Kiyoto; Shimizu, Yasushi; Sugasawa, Masashi; Tahara, Makoto; Takahashi, Masanobu; Takahashi, Shunji; Tanaka, Kaoru; Ueda, Tsutomu; Yamaguchi, Hironori; Yamazaki, Tomoko; Yasumatsu, Ryuji; Yokota, Tomoya; Yoshizaki, Tomokazu; Kudaba, Iveta; Stara, Zinaida; Ishak, Wan Zamaniah Wan; Cheah, Soon Keat; Ponce, Jose Aguilar; Mendoza, René González; Hernández, Carlos; Soto, Francisco; Buter, Jan; Hoeben, Ann; Oosting, Sjoukje F.; Suijkerbuijk, Karijn P M; Bratland, Å.; Brydoey, Marianne; Alvarez, Renzo; Más, Luís; Caguioa, Priscilla B.; Querol, J. Marruecos; Regala, Eugenio Emmanuel; Tamayo, Maria Belen; Villegas, Ellie May; Kawecki, Andrzej; Karpenko, Andrey; Клочихин, А. Л.; Smolin, A.; Zarubenkov, Oleg; Goh, Boon Cher; Cohen, G.; Toit, Johanna du; Jordaan, Christa; Landers, Gregory; Ruff, Paul; Szpak, Waldemar; Tabane, Neonyana Keorapetse Rebecca; Braña, Irene; Docampo, Lara Iglesias; Lavernia, Javier; Mesı́a, Ricard; Abel, Edvard; Muratidu, Valentina; Nielsen, Niels Hilmer; Cristina, Valérie; Rordorf, Tamara; Rothschild, Sacha I.; Hong, Ruey‐Long; Wang, Hung‐Ming; Yang, Muh‐Hwa; Yeh, Su‐Peng; Yen, Chia-Jui; Ngamphaiboon, Nuttapong; Soparattanapaisarn, Nopadol; Sriuranpong, Virote; Aksoy, Sercan; Çiçin, İrfan; Ekenel, Meltem; Harputluoğlu, Hakan; Ozyilkan, Ozgür; Harrington, Kevin J.; Agarwala, Sanjiv S.; Ali, Haythem; Alter, Robert S.; Anderson, D. Mark; Bruce, Justine Y.; Burtness, Barbara; Campbell, Nicholas; Conde, Miguel Á.; Deeken, John F.; Edenfield, W. Jeff; Feldman, Lawrence E.; Gaughan, Elizabeth M.; Goueli, Basem; Halmos, Balázs; Hegde, Upendra P.; Hunis, Brian; Jotte, Robert M.; Karnad, Anand B.; Khan, Saad A.; Laudi, Noel; Laux, Douglas; Martincic, Danko; McCune, Steven L.; McGaughey, Dean; Misiukiewicz, Krzysztof; Mulford, Deborah; Nadler, Eric; Neupane, Prakash; Nunnink, Johannes C.; Ohr, James; O’Malley, Meaghan; Brian, Patson; Paul, Doru; Popa, E; Powell, Steven; Redman, Rebecca; Rella, Vincent; Lima, Chaio Rocha; Sivapiragasam, Abirami; Su, Yungpo Bernard; Sukari, Ammar; Wong, Stuart J.; Yilmaz, Emrullah; Yorio, Jeffrey T.

doi:10.1016/s0140-6736(19)32591-7

Cited by 2,194 publications

(1,861 citation statements)

References 24 publications

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“…For HPV-negative HNSCC, about 50% of patients with locally advanced and almost all with distant disease succumb to this cancer. Therapeutic options have expanded recently, but even so, the majority of patients experience progression after chemotherapy, immune checkpoint inhibition, or the combination [2]. Notably, the most common genetic lesion in HPV-negative HNSCC is mutation of the tumor suppressor TP53 [3], which occurs in >85% of tumors and disrupts a central component of the G1/S checkpoint machinery.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Deneka

Einarson

Bennett

et al. 2020

Cancers

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Head and neck squamous cell carcinomas (HNSCC) affect more than 800,000 people annually worldwide, causing over 15,000 deaths in the US. Among HNSCC cancers, human papillomavirus (HPV)-negative HNSCC has the worst outcome, motivating efforts to improve therapy for this disease. The most common mutational events in HPV-negative HNSCC are inactivation of the tumor suppressors TP53 (>85%) and CDKN2A (>57%), which significantly impairs G1/S checkpoints, causing reliance on other cell cycle checkpoints to repair ongoing replication damage. We evaluated a panel of cell cycle-targeting clinical agents in a group of HNSCC cell lines to identify a subset of drugs with single-agent activity in reducing cell viability. Subsequent analyses demonstrated potent combination activity between the CHK1/2 inhibitor LY2606268 (prexasertib), which eliminates a G2 checkpoint, and the WEE1 inhibitor AZD1775 (adavosertib), which promotes M-phase entry, in induction of DNA damage, mitotic catastrophe, and apoptosis, and reduction of anchorage independent growth and clonogenic capacity. These phenotypes were accompanied by more significantly reduced activation of CHK1 and its paralog CHK2, and enhanced CDK1 activation, eliminating breaks on the mitotic entry of cells with DNA damage. These data suggest the potential value of dual inhibition of CHK1 and WEE1 in tumors with compromised G1/S checkpoints.

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Section: Introductionmentioning

confidence: 99%

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Deneka

Einarson

Bennett

et al. 2020

Cancers

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“…To further elucidate the inherent correlations between immunologic phenotypes and distinct prognostic outcomes, the curated gene list of immune modulators was adopted [15], of which the correlogram was suggestive of evident collections consisted of these immune-related components. With the in-depth illustration of immunoediting theory and evolution of immunotherapy, immune checkpoints have been considered with cruciality in cancer immunity response, and the developed inhibitors have been dramatically improving the prognosis of several types of malignancies [21][22][23]. Herein, immune checkpoints were selected to be evaluated between these two pIRS groups.…”

Section: Discussionmentioning

confidence: 99%

Tumor microenvironment subtypes and immune-related signatures for the prognosis of breast cancer

Wang

Xu²

2020

Preprint

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To better understand the heterogeneity of tumor microenvironment (TME) and establish a prognostic model for breast cancer in clinical practice, the leukocyte infiltrations of 22 cell types of interest from 2620 breast cancer patients were quantitatively estimated using deconvolution algorithms, and three TME subtypes with distinct molecular and clinical features were identified by unsupervised clustering approach. Then, we carried out systematic analyses to illustrate the contributing mechanisms for differential phenotypes, which suggested that the divergences were distinguished by cell cycle dysfunction, variation of cytotoxic T lymphocytes activity. Next, through dimensionally reduction and selection based on random-forest analysis, least absolute shrinkage and selection operator (LASSO) analysis, and uni- and multivariate COX regression analysis, a total of 15 significant genes were proposed to construct the prognostic immune-related score (pIRS) system and, in combinations with clinicopathological characteristics, a predictive model was ultimately built with well performance for survival of breast cancer patients. Comparative analyses demonstrated that proactivity of CD8 T lymphocytes and hyper-angiogenesis could be attributed to distinct prognostic outcomes. In conclusion, we retrieved three TME phenotypes and the curated prognostic model based on pIRS system for breast cancer. This model is justified for validation and optimized in the coming future.

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“…However, over 65% of the patients who received this chemotherapy and immunotherapy combination continued to have progressive disease (15). Similarly, the KEYNOTE-048 trial, performed in patients with recurrent unresectable HNSCC in which the tumor contained greater than 1% of cells staining positively for PD-L1 failed to show any improvement in progression-free survival in patients treated with cisplatin or carboplatin, 5-FU, and pembrolizumab, compared to those treated with the same chemotherapy plus cetuximab, although there was an increase in median overall survival from 10.7 months to 13 months when pembrolizumab was included in the combination (16). Clearly, identifying mechanisms that would enhance response rates to the combination of immune checkpoint blockade and chemotherapy, and prolong the durability of the response, remains an unmet clinical need.…”

Section: Introductionmentioning

confidence: 97%

“…However, early combination of chemotherapy with immune checkpoint inhibitors as a first line therapeutic modality was recently approved for EGFR, ALK, and ROS negative nonsmall cell lung cancer (NSCLC) using cisplatin and pembrolizumab (15), and for head and neck squamous cell carcinomas (HNSCC) using platinum agents, 5-FU, and pembrolizumab (16).…”

Section: Introductionmentioning

confidence: 99%

The Injury Response to DNA Damage Promotes Anti-Tumor Immunity

Sriram

Milling

Chen

et al. 2020

Preprint

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The authors declare no potential conflicts of interest.DNA damage-induced live injured cell adjuvant Sriram et al. ABSTRACTInhibition of immune checkpoints has shown promising results in the treatment of certain tumor types. However, the majority of cancers do not respond to immune checkpoint inhibition (ICI) treatment, indicating the need to identify additional modalities that enhance the response to immune checkpoint blockade. In this study, we identified a tumor-tailored approach using ex-vivo DNA damaging chemotherapy-treated tumor cells as a live injured cell adjuvant. Using an optimized ex vivo system for dendritic cellmediated T-cell IFN-γ induction in response to DNA-damaged tumor cells, we identified specific dose-dependent treatments with etoposide and mitoxantrone that markedly enhance IFN-g production by T-cells. Unexpectedly, the immune-enhancing effects of DNA damage failed to correlate with known markers of immunogenic cell death or with the extent of apoptosis or necroptosis. Furthermore, dead tumor cells alone were not sufficient to promote DC cross-presentation and induce IFN-g in T-cells. Instead, the enhanced immunogenicity resided in the fraction of injured cells that remained alive, and required signaling through the RIPK1, NF-kB and p38MAPK pathways. Direct in vivo translation of these findings was accomplished by intra-tumoral injection of ex vivo etoposide-treated tumor cells as an injured cell adjuvant, in combination with systemic anti-PD1/CTLA4 antibodies. This resulted in increased intra-tumoral CD103 + dendritic cells and circulating tumor antigen-specific CD8 + T-cells, leading to enhanced anti-tumor immune responses and improved survival. The effect was abrogated in BATF3-deficient mice indicating that BATF3 + DCs are required for appropriate T-cell stimulation by live but injured DNA-damaged tumor cells. Notably, injection of the free DNA-damaging drug directly into the tumor failed to elicit such an enhanced anti-tumor response as a consequence of simultaneous damage to dendritic cells and T-cells. Finally, the DNA damage induced injured cell adjuvant and systemic ICI combination, but not ICI alone, induced complete tumor regression in a subset of mice who were then able to reject tumor re-challenge, indicating induction of a long-lasting anti-tumor immunological memory by the injured cell adjuvant treatment in vivo. DNA damage-induced live injured cell adjuvant Sriram et al.

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Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Cited by 2,194 publications

References 24 publications

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Tumor microenvironment subtypes and immune-related signatures for the prognosis of breast cancer

The Injury Response to DNA Damage Promotes Anti-Tumor Immunity

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