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ONCAlert | Upfront Therapy for mRCC
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CRC Field Moves Toward Unique, Tailored Approaches

Brandon Scalea
Published Online:8:46 PM, Wed May 1, 2019

Michael J. Overman, MD

Identifying molecular alterations in metastatic colorectal cancer (mCRC) has become crucial as a way to help inform which treatment strategy will result in the best outcome for each patient, said Michael J. Overman, MD.

For example, patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) disease may benefit from immunotherapy, which has shown dramatic, durable responses with curative potential in this rare subset of patients with mCRC.

“The numbers are fairly small on this front but it's clear that we are curing a fraction of [patients with] mCRC,” said Overman. “It behooves us as practitioners to identify these patients because it's a remarkable change in our standard approach. That's the most exciting thing about this MSI-H mCRC space.”

In the phase II CheckMate-142 trial, 119 patients with MSI-H/dMMR mCRC were treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy). Initial results showed an objective response rate (ORR) of 49% and the median duration of response had not been reached. These data led to the FDA’s decision to grant accelerated approval to the combination for the treatment of patients with MSI-H or dMMR mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan in July 2018.

Updated data from the CheckMate-142 trial, which were presented at the 2019 Gastrointestinal Cancers Symposium, showed that a median follow-up of 25.4 months, the combination elicited a 58% ORR, and the median progression-free and overall survival were not reached.2 Next steps for the regimen include further evaluation in the frontline setting.

In an interview with Targeted Oncology, Overman, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed this combination regimen in mCRC and highlighted existing challenges that still need to be addressed in future research.

TARGETED ONCOLOGY:  What does the treatment landscape of mCRC look like?

Overman: The field of mCRC has become unique in that there are many different molecular subsets that we utilize. The first key statement in the mCRC landscape is molecular subset. [A patient] gets MSI testing, BRAF testing, RAS testing, and HER2 has emerged as an important [biomarker] as well. Clearly, there are a lot of exciting data with immunotherapy in MSI-H or dMMR CRC, so that's a subset we need to identify because we have therapies for them. We are utilizing this in the second- and third-line settings and beyond, and there are trials ongoing looking at the frontline setting. BRAF V600E is a mutation where we have National Comprehensive Cancer Network (NCCN) guideline-based therapy of vemurafenib (Zelboraf), cetuximab (Erbitux), and irinotecan. There are potentially emerging data coming with the BEACON CRC study, a big ongoing phase III trial in this space.

For patients with RAS mutations, we've known for a while that they have to be RAS wild-type in order to benefit from anti-EGFR therapy, so that marker has to be collected as well. There are ongoing studies looking at the HER2 space, but there is nothing in terms of guidelines right now. When we use combination approaches for HER2 targeting, we see a lot of activity. These are the key fundamentals you have to sort out to understand our unique approaches going forward. Our frontline setting still consists of the typical systemic chemotherapy of FOLFOXIRI, FOLFIRI, and others with a biologic depending on molecular profiling and sidedness.

TARGETED ONCOLOGY:  What data have we seen with immunotherapy?

Overman: This [approach] is for the MSI-H or dMMR subset of mCRC, which represents about 4% to 5% of this disease. However, it's a group that has consistently shown good data with immunotherapy. We have seen data with pembrolizumab (Keytruda), an anti–PD-1 agent, nivolumab as a single agent, and now, the combination of nivolumab plus ipilimumab. This combination has also shown dramatic benefit. The CheckMate-142 study had 114 patients with relapsed mCRC treated with that combination. That demonstrated remarkable results of a 50% response rate and a progression-free survival benefit that appears consistent at about 70% at 1 year. It's a high level of activity that appears durable, so this is very exciting. The CheckMate-142 study had another part to it that was presented at the 2018 ESMO Congress, which asked the question of whether we could give this combination in the upfront setting. We saw similar activity of what you would see in the refractory setting.

In the frontline setting, we don't have any large randomized trials to look at presently, but there is one that is ongoing with pembrolizumab that will potentially read out either this year or next. This may help set the standard for the frontline setting with a randomized study behind it.

TARGETED ONCOLOGY:  What is the clinical significance of these data in MSI-H mCRC?

Overman: The most significant thing is that we have these new options for patients with MSI-H mCRC. These drugs are approved after fluoropyrimidine, oxaliplatin, irinotecan-based chemotherapy. NCCN guidelines recommend [immunotherapy] as a second-line therapy. I think we should be identifying all of these patients to recognize the subset that [can benefit from] this effective therapy. In part, I say that because the early data with this therapy suggest that when it works, it can really be curative in a subset of patients. It is reducing the cancer and generating durable responses; patients can stop therapy and the cancer does not come back.

TARGETED ONCOLOGY:  What are the biggest challenges that still exist in this space?

Overman: The biggest challenge is that we see a high level of activity when we look at monotherapy or combination therapy, but there's still a subset of patients that are not responding. This subset has a high mutation load and a lot of neoantigens. They have a lot of pro-immunologic components, so you would think that all MSI-H patients should be responding to immunotherapy. Clearly, there are other mechanisms at play that prevent our current therapies from working. The real open question that remains is what these other mechanisms are. Can we identify these clearly and then engage on them to move this great response rate even higher? There is a lot of hope that we can do this. Right now, it's a lot of sample translational analysis. There hasn't been a consistent answer to this, so it's a work in progress. 
 
 
 
References:
  1. Bristol-Myers Squibb’s Opdivo ® (nivolumab) + Low-Dose Yervoy ® (ipilimumab) is the First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a Fluoropyrimidine, Oxaliplatin and Irinotecan. Published July 11, 2018. Access July 11, 2018. https://bit.ly/2uaofBD.
  2. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Long-term follow-up. J Clin Oncol. 2019;37(suppl; abstr 635).


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