Optimal Treatment of Chemoresistant mCRC - Episode 7

IMblaze370 Trial in MSS mCRC

March 13, 2019

Tanios Bekaii-Saab, MD, FACP:There are certain subgroups of colorectal cancer that we know may benefit from either targeted agents or immune therapeutics. We know the NTRK fusion’s a good story across all solid tumors. If you have that NTRK fusion, you have a great response. And we have agents, 1 agent that’s approved, larotrectinib which is approved essentially in all solid tumors that express NTRK fusion. In colorectal cancer, a rate of .3% to .7% may have that fusion.

Immune therapy, which, as we know, has made strides in a lot of different cancers, is also available to our patients in colon cancer for those with MSI [microsatellite instable]-high phenotype. Those are the patients, that’s about 4% of all your metastatic colorectal cancer that have a significant and meaningful response to agents like pembrolizumab, nivolumab. And 1 study suggests perhaps adding ipilimumab to nivolumab may also have benefit. That’s CheckMate-142. So we know that there is a subgroup of patients with MSI-high and about two-thirds of them will have very good response, and about half of them will have not just a very good response but a very durable response. So it’s very important to understand that.

Now, other cancers have immune therapy options like melanoma, lung cancer, and others that apply to a number of patients beyond just a specific biomarker, typically PD-L1 [programmed death-ligand 1] would help you to select in those patients but there may be others as well. So, in colorectal cancer, for the last few years, we’ve been hoping to find an entry point for these immune therapeutic agents and to the microsatellite stable. So those patients where we know a single-agent PD-1 does not seem to help.

Now, it’s important to understand why PD-1 inhibitors or CTLA4 [cytotoxic T-lymphocyte—associated antigen 4] inhibitors, on their own or even combined, don’t show much activity in the microsatellite stable. It’s because those tumors are not very inflamed. They’re not very hot. They have very few mutations. They’re not very apparent to the immune system. And so the whole work that at least preclinically has been done about how can we make those tumors more inflamed and more visible to the immune system.

So one of those strategies was with applying a MEK [mitogen-activated protein kinase kinase enzymes] inhibitor to the milieu which seems to essentially invite some of these tumor infiltrating lymphocytes into the tumor and then allow PD-1, PD-L1 inhibitors to amplify their effect, and thus you see more activity. An early phase IB study suggested that the combination of a MEK inhibitor called cobimetinib and atezolizumab which is essentially a PD-L1 inhibitor, when you combine the 2, that you do see a certain level of response in disease where you see almost no responses from immune therapy.

So this went to the IMblaze370 study comparing cobimetinib to atezolizumab versus atezolizumab versus regorafenib in patients with microsatellite stable metastatic colorectal cancer. What that study suggested essentially is that there’s lack of benefit, which is very unfortunate, for combining cobimetinib to ATEZO [atezolizumab]. And ATEZO itself didn’t have much activity. Interestingly, regorafenib actually seemed to have a superior median progression-free survival to the immunotherapeutic options but very consistent with historical controls. So, unfortunately, that first entry point for immune therapy into microsatellite stable tumors did not pan out, at least did not seem to be superior to regorafenib.

Transcript edited for clarity.

Case: A 60-Year-Old Male With mCRC

Initial presentation

April 2015

  • A 60-year—old man was referred to gastroenterology after complaining of general malaise and alternating constipation with bloody diarrhea.
  • PE: Showed left-sided lower abdominal pain
  • Carcinoembryonic antigen (CEA); 8.1 mg/L
  • Colonoscopy revealed a left-sided adenocarcinoma of the colon
  • Surgery: left hemicolectomy
  • Pathology: well-differentiated adenocarcinoma
  • PET/CT: 15/15 lymph nodes tested negative
  • Staging: IIIA
  • ECOG PS 0
  • Patient received adjuvant mFOLFOX4

April 2018

  • 24 months later, the patient complained of mild abdominal distension and his stools were pencil-shaped with some presence of blood
  • PET/CT scan showed widespread small liver lesions
  • CEA; 14.7 mg/L
  • Biopsy was CK2-positive
  • Molecular testing; allRAS&BRAFWT
  • ECOG PS 1
  • Patient began treatment with FOLFIRI + bevacizumab

February 2019

  • PET/CT scan showed evidence of new liver lesions and a 2-cm mass in the right lung
  • CEA; 31.7 mg/L
  • Patient started on regorafenib 80 mg/day