Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial

Eng, Cathy; Kim, Tae Won; Bendell, Johanna C.; Argilés, Guillem; Tebbutt, Niall C.; Bartolomeo, Maria Di; Falcone, Alfredo; Fakih, Marwan; Kozloff, Mark; Sobrero, Alberto; Yan, Yibing; Chang, Ilsung; Uyei, Anne; Roberts, Louise; Ciardiello, Fortunato; Ahn, JB; Asselah, Jamil; Badarinath, Suprith; Baijal, Shobhit; Begbie, Steven; Berry, Sneha; Canon, J. R.; Carbone, RG; Cervantes, Andrés; Cha, YJ; Chang, Karen; Chaudhry, Arvind; Chmielowska, Ewa; Cho, Seung-Hun; Chu, David; Couture, Félix; Cultrera, Jennifer L.; Cunningham, David; Cutsem, Éric Van; Cuyle, P J; Davies, Janine Marie; Dowden, Scot; Dvorkin, Mikhail; Ganju, Vinod; Garcia, RV; Kerr, David J.; Ty, Kim; King, Kevin G.; Kortmansky, Jeremy; Lam, Kwok Fai; Lee, J; Lee, AS; Bernard, Loris; Luppi, Gabriele; Ma, Ben; Maiello, Evaristo; Mandanas, Romeo A.; Marshall, J. L.; Marx, Gavin; Mullamitha, Saifee; Nechaeva, Marina; Jo, Park; Pavlakis, Nick; Ponce, CG; Potemski, Piotr; Raouf, Sherif; Reeves, James A.; Segal, Neil H.; Siena, Salvatore; Smolin, A.; Streb, JO; Strickland, A. H.; Szutowicz-Zielińska, Ewa; Tabernero, Josep; Tan, Benjamin; Valera, JS; Eynde, Marc Van den; Vergauwe, Philippe; Vickers, Michael M.; Womack, Mark; Wróblewska, Marta; Young, Ruth T.

doi:10.1016/s1470-2045(19)30027-0

Cited by 417 publications

(314 citation statements)

References 29 publications

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“…Concordantly, we also observed PD-L1 change with recruitment of intratumoral CD8 + lymphocytes following selumetinib/docetaxel treatment. Although a recent cobimetinib/atezolizumab trial has failed to show survival benefit in patients with MSS colorectal cancer (47), selumetinib and anti-PD-1 treatment may be explored in patients with MSS gastric cancer. Congruently, this highlights the nonstatic nature of PD-L1 as a selection biomarker and suggests combination and/or sequential strategies are worth exploration.…”

Section: Discussionmentioning

confidence: 99%

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

et al. 2019

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The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RIC-TOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE:Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility.

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Section: Discussionmentioning

confidence: 99%

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

et al. 2019

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“…MEK is a promising target for KRAS, NRAS, and BRAF mutant tumors and is being targeted in CRC (260). Recently, MEK inhibitor, cobimetinib, combined with anti-PD-L1 therapy (atezolizumab) failed to improve survival in microsatellite-stable metastatic CRC patients in a phase 3 clinical trial (261). Could the inclusion of A2AR antagonists be key to the success of these studies?…”

Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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“…Thereinto, 1,936 records were screened by the title and abstract after removing the duplicates. Eventually, 26 studies with 6,896 unique individuals were collected following perusing the full texts (Antonia et al, 2016;Fehrenbacher et al, 2016;Balar et al, 2017;Peters et al, 2017;Powles et al, 2017;Barlesi et al, 2018;Choueiri et al, 2018;Dirix et al, 2018;Garassino et al, 2018;Horn et al, 2018;Liu et al, 2018;McDermott et al, 2018;Pal et al, 2018;Patel et al, 2018;Powles et al, 2018;Schmid et al, 2018;Siu et al, 2018;Socinski et al, 2018;Spigel et al, 2018;Chung et al, 2019;Eng et al, 2019;Hong et al, 2019;Kim, 2019;Motzer et al, 2019;Rini et al, 2019;West et al, 2019). In sum, 74 cases of fatal adverse events associated with PD-L1 inhibitors were documented.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…Additionally, two studies included all patients with a positive status of PD-L1 (Peters et al, 2017;Spigel et al, 2018), whereas only one study that PD-L1 status was a negative status (Siu et al, 2018). Each of the following five kinds of cancers only included a qualified article: SCLC, pancreatic cancer, colorectal cancer, gastric or gastroesophageal junction cancer, and head and neck squamous cell carcinoma (HNSCC) (Horn et al, 2018;Siu et al, 2018;Chung et al, 2019;Eng et al, 2019;Hong et al, 2019). A detailed characteristic of 26 studies was presented in Table 1.…”

Section: Study Characteristicsmentioning

confidence: 99%

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis

Wang

Chen

et al. 2020

Front. Pharmacol.

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Purpose: We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events.Method: PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemiplimab".Results: A total of 26 eligible studies were identified, incorporating 6,896 unique participants. The overall incidence was 1.24% (95% CI: 0.93-1.65%). The incidence and odds were higher in patients with non-squamous non-small cell lung cancer (NSCLC) than those with urothelial carcinoma [(2.25 vs. 0.85, p = 0.04), (odds ratio [OR]: 2.69; 95% CI: 1.04-6.97, p = 0.04)], higher in the middle-aged group than the young group [(1.74 vs. 0.89, p = 0.01), (OR: 2.13; 95% CI: 1.26-3.61, p = 0.01)], and higher in the trial phase I than the trial phase II [(1.76 vs. 0.60, p = 0.01), (OR: 0.31; 95% CI: 0.13-0.75, p = 0.01)]. Notably, the trial phase I had a higher incidence than trial phase II or III following regulating for cancer types and average age (OR: 0.28; 95% CI: 0.11-0.71, p = 0.01, OR: 0.48; 95% CI: 0.24-0.95, p = 0.04, respectively). In terms of organ-specific fatal adverse events, interstitial lung disease (ILD) was frequently documented. A variety of respiratory systemrelated fatal adverse events were recorded, including but not limited to pneumonia and respiratory failure. As for organ-unspecific fatal adverse events, substantial cases of sepsis and neutropenia were recorded. Conclusion:This study firstly provided a comprehensive incidence and the spectrum of fatal adverse events associated with PD-L1 inhibitors, and identified three potential susceptible factors of that, yielding a capability for clinicians to distinguish high-risk Frontiers in Pharmacology | www.frontiersin.org

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Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial

Cited by 417 publications

References 29 publications

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis

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