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Expert Discusses PD-1 Success in MSI-H Colorectal Cancer

Angelica Welch
Published: Thursday, Feb 09, 2017

Michael J. Overman, MD

Michael J. Overman, MD

The latest clinical trial data strongly support anti–PD-1 therapy as the new second-line treatment standard for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), says Michael J. Overman, MD.

Overman is the lead author of the phase II CheckMate-142 study, which examined single-agent nivolumab (Opdivo) or nivolumab combined with ipilimumab (Yervoy) in patients with recurrent or mCRC, who were either MSI-H or microsatellite stable. At the 2017 Gastrointestinal (GI) Cancers Symposium, Overman presented results from the trial for 74 patients with MSI-H mCRC treated with nivolumab monotherapy.

The overall response rate in these patients was 31.1%, the 12-month progression-free survival rate was 48.4%, and the 12-month overall survival rate was 73.8%. Results are not yet available for the cohort of patients with MSI-H mCRC who are receiving nivolumab plus ipilimumab.

In an interview with OncLive at the 2017 GI Symposium, Overman, associate professor, The University of Texas MD Anderson Cancer Center, discussed the significance of the ongoing CheckMate-142 study and the next steps in MSI-H mCRC.

OncLive: How common is MSI-H in mCRC and what does it mean for those patients?

Overman: MSI-H is a subset of CRC in the metastatic setting—about 4% or 5% of metastatic patients. We've known for a while that this set of patients have been immune-recognized—they tend to have a high mutation load based on the genesis of those cancers as a deficiency in DNA repair. This means they have a high level of mutations, likely conferring they have a high level of neoantigens. When something is mutated, it is foreign, meaning it hasn’t been seen by the patient’s immune system before so it can be immune-recognized. This idea of high mutations/high neoantigen load makes up MSI-H mCRC.

That’s the reason this study was initiated—based on the premise that patients would have a high level of mutations that would be recognized by the immune system. It’s also known that these tumors have high checkpoint expressions, so it appears that these tumors are trying to turn off the immune system and by providing therapy we hope to unleash an intrinsic immune response. I think our study demonstrates that the tumors are doing this.

Can you give an overview of CheckMate-142?

It is a phase II study that explores 2 different strategies. One is combination therapy with nivolumab and ipilimumab and the other is monotherapy with nivolumab. It was designed as a 2-stage study, so it has a first stage with monotherapy and then based off a high-level response rate, it proceeds to the second stage.

We showed results for the 74 patients who received monotherapy with nivolumab. The second cohort treated with combination therapy was still enrolling at the time of the database lock for this presentation. We presented the six-month updated analysis from the initial presentation at ASCO 2016 on monotherapy.

What did the updated findings show?

The updated findings reflect the further duration of evaluation, which supports some of our early findings where we saw a high response rate of stable disease in patients that we treated. We see approximately 2 out of 3 of patients having clinical benefit.

The exciting thing about this data is that patients who have stable disease or responses, appear to be durable. The data shows that over 80% of patients who had a response are still on therapy. We see the same thing with stable disease—if a patient has stable disease that lasts over 4 months, the majority of them are still on therapy. So, this follow-up demonstrated the durability of that benefit in these patients.

The second factor that we discussed that we haven't before is looking at some of the clinical factors of relevance and biomarkers. We showed that PD-L1 expression is seen in about 1 out of 4 cases (≥1%), but responses are irrespective of PD-L1 expression. Additionally, we show that responses are irrespective of BRAF mutation or a clinical history of Lynch syndrome.




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