Anti-PD-L1 immunotherapy responsive in microsatellite-stable mCRC comb with MEK inhibition
BARCELONA-LUGANO, 29 June 2016 – Anti-PD-L1 immunotherapy may achieve a response in patients with microsatellite-stable metastatic colorectal cancer if combined with a MEK inhibitor, according to phase I data presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.
"So far, immunotherapy has only shown activity in patients with microsatellite instability-high colorectal cancer, which is only 5% of the population," says the study's (1) principal investigator Dr Johanna Bendell, from the Sarah Cannon Research Institute and Tennessee Oncology, in Nashville, Tennessee.
Microsatellite instability-high colorectal cancers are associated with a greater number of mutations and are therefore more responsive to immunotherapy with PD-L1/PD-1 blockade. However the majority of patients with metastatic colorectal cancer – around 95% – have microsatellite-stable disease that so far has shown almost no response to immunotherapy.
Preclinical studies have suggested that a MEK inhibitor can make a tumor more responsive to immunotherapy by increasing the number of active immune cells – such as CD8+ cells – in the tumor, and increasing the expression of factors that cause the immune system to be more active.
In this phase 1b study, 23 previously-treated patients with metastatic colorectal cancer were treated with escalating doses of MEK inhibitor cobimetinib (20mg, 40mg, and 60mg daily, 21 days on, 7 days off), with an expansion of patients at the highest dose level, and a 800mg dose of intravenous PD-L1 inhibitor atezolizumab every two weeks.
Following treatment, researchers saw a decrease of at least 30% in tumor size in four patients (17%) and stable disease in five patients (22%). The duration of responses ranged from 4 months to over 15 months, and were still ongoing in two of four patients who were partial responders at the time of the data cut.
Three of the partial responders had microsatellite-stable or microsatellite instability-low disease and one had unknown microsatellite status. None of the patients in the study had known microsatellite high disease.
The baseline PD-L1 status did not appear to affect responses, and the combination was well tolerated with no serious treatment-related adverse events reported.
In summary, Dr Bendell says, "What we saw is consistent with the hypothesized mechanism of action of this combination, which shows promise in giving the other 95% of colon cancer patients a chance to respond to immunotherapy." Researchers have now launched a randomized phase III study to compare the combination with standard treatment for patients with refractory metastatic colorectal cancer.
Commenting on the findings, Professor Florian Lordick, Director of the University Cancer Centre Leipzig, Germany, says "this important phase 1b study now shows for the first time that metastatic colorectal cancer can be sensitized for immune therapy by inhibition of MEK-dependent intracellular signaling."
"This is the first step for immunotherapy to reach patient populations who previously were not identified as good candidates for immune checkpoint inhibition," Professor Lordick says.
Notes to Editors
1 Abstract LBA-01 – 'Safety and efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer (mCRC)' will be presented by Johanna Bendell during Session I: Opening, Selected Abstracts, and Lectures on Nutrition on Wednesday 29 June, 14:50 (CEST).
Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.
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Safety and efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer (mCRC)
Johanna Bendell,1 Tae Won Kim,2 Cheng Ean Chee,3 Yung-Jue Bang,4 Carrie Lee,5 Jayesh Desai,6 Jeremy Lewin,7 Jeffrey Wallin,8 Meghna Das Thakur,8 Grace Mwawasi,8 Edward Cha,8 Jeffrey Infante1
1 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
2 Asan Medical Center, Seoul, South Korea
3 Cancer Science Institute of Singapore, National University of Singapore, Singapore
4 Seoul National University Hospital, Seoul, South Korea
5 UNC Lineberger Comprehensive Cancer Center, University of North Carolina – Chapel Hill, North Carolina
6 Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
7 Princess Margaret Cancer Center, University Health Network, Toronto, Canada
8 Genentech, Inc., South San Francisco, CA
Background: Microsatellite instability-high (MSI-H) colorectal cancers are associated with high mutation burden and are responsive to PD-L1/PD-1 blockade. However, the majority of mCRC pts are MSS and have lower response rates to PD-L1/PD-1 blockade. Although MEK inhibition has minimal activity in mCRC, preclinical models demonstrate intratumoral T cell accumulation with MEK inhibition and durable tumor regression when combined with anti-PDL1. Therefore, we evaluated the combination of cobi (MEK inhibitor) and atezo (anti-PDL1) in patients (pts) with mCRC.
Methods: A Phase 1b dose escalation and expansion study treated advanced solid tumor pts with 20, 40, and 60mg cobi daily (21d on / 7d off) in combination with a fixed dose of 800mg atezo IV q2w. The expansion dose was 60mg cobi and 800mg atezo. Safety and preliminary investigator-assessed efficacy by RECIST v1.1 were assessed. As of Oct 12, 2015, the study enrolled 23 previously treated mCRC pts, including 22 KRASmt and 1 KRASwt, without selection for MSI-H status or PD-L1 expression.
Results: No DLTs, treatment-related G4, or any G5 AEs were identified. G3 AEs related to study treatment were reported in 8 pts (35%). The most common AEs of any grade were rash, diarrhea, and fatigue. The median safety follow-up was 3.78 mo (range, 1.1-11.7). There were 4 confirmed PRs (17%) and 5 SDs. Duration of response ranged from 4.0 to 7.7 mo and responses were ongoing in 3 of 4 pts at time of data cutoff. Baseline PD-L1 expression did not correlate with activity. No MSI-H pts were identified among the responders. 3 PRs were MSS or MSI-low by local testing. The MSI status of 1 PR was unknown. Biomarker data suggest enhanced immune response with the combination.
Conclusions: These early results show that anti-PDL1 immunotherapy can be active in the broader MSS mCRC population when combined with MEK inhibition. Cobi and atezo is a rational and tolerated regimen to investigate further in MSS mCRC. NCT01988896
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