Key Trials in mCRC: I/O Combination Therapies

Axel Grothey, MD: IMblaze370 gives us a lot of lessons to be learned because everyone was excited about the design of the study, based on pretty limited initial data, a phase 1b study, which looked at the combination of cobimetinib-atezolizumab, a MEK inhibitor plus a PD-L1 inhibitor in the later-line setting in about 20 patients with MSS [microsatellite stability]. Most of them had MSS tumors, and we saw 4 responses: 3 were really MSS tumors, and 1 we didn’t know what the MSI [microsatellite instability] status was. This created a lot of excitement, initially. Everyone wanted to make immunotherapy work in these otherwise immunotherapy-refractory colorectal cancers, and there was some preclinical rationale. There was the idea of recruiting T cells into the tumor through the MEK inhibition, making these T cells be more sustainable, have durable activity, etc. They have a lot of data that led to the idea of running a phase 3 study. Well, the phase 3 study eventually accrued very rapidly. It was an international effort to randomize patients to atezolizumab-cobimetinib versus atezolizumab alone versus regorafenib as the control arm, which was used because it was considered an easy arm to beat, based on toxicity profile and limited activity. The study eventually came out negative. There was no difference in outcome between the combination of atezolizumab-cobimetinib or atezolizumab alone compared with regorafenib. In fact, regorafenib outperformed expectations and now is being cited for being associated with overall survival of about 8.5 months in the later-line, phase 3 setting. That’s encouraging to know we have an active agent, even in modern times, that held its ground in a phase 3 setting.

The lessons learned are several. First, we move very rapidly from limited data in phase 1b to expanding into a phase 3 study, and we need to be very careful with future endeavors to have better signals. This is also important right now for the excitement people have based on some limited data on regorafenib plus nivolumab. Are the data from Japan in gastric cancer and colorectal cancer really enough to warrant a phase 3 study? Particularly when, now, single-arm studies from other institutions do not seem to be able to completely replicate these data. It’s a very important point to be careful in the development to see what patients could benefit from this combination.

This other part is that cobimetinib-atezolizumab not only did not beat regorafenib but is also more toxic. A lot more patients, 2 times more patients, went off therapy with cobimetinib-atezolizumab, compared with regorafenib, because of adverse effects. So it’s not just that this drug didn’t work. We might have also potentially harmed some patients, at least with adverse effects. All this shows how important it is to have good data that allow us to move combination therapy, immunotherapy combinations, into a later-line setting, into phase 3. People are more careful now. On the other hand, everyone recognizes that if we can make MSS colorectal cancer immunogenic, that would be a home run. It’s the holy grail of immunotherapy because it’s a very common and very immunotherapy-refractory cancer so we all want to make sure we find, eventually—and I’m sure we will—find ways to treat MSS cancers with immunotherapy.

Fortunato Ciardiello, MD, PhD: There are several possibilities in metastatic colorectal cancer to try to enhance the immune response in the vast majority of metastatic colorectal cancer patients whose tumors are microsatellite stable. These tumors we know could be either immune desert or immune inflamed. Both conditions are not the best conditions for the conventional I/O like anti–PD-1 or anti–PD-L1 antibodies to work. In the past, we had some hope that inhibiting MEK pathway will enhance in these patients the activity of PD-L1 antibodies. This strategy unfortunately failed. What has been now tried to be done is a dual approach. One is in RAS/RAF wild-type patients, trying to combine anti-EGFR monoclonal antibodies and most likely cetuximab, also because it is an ADCC [antibody-dependent cell-mediated cytotoxicity] potential immunoglobulin inducer with anti–PD-1 or anti–PD-L1 antibodies.

There are some studies that are ongoing also in colorectal cancer. Some are ongoing with these combinations in head and neck squamous cell carcinoma, and some have been done also in non–small cell lung cancer. Another opportunity has been to try to combine immuno-oncology drugs, such as PD-1 or PD-L1 inhibitors, with antiangiogenic drugs. For example, we know that the combination of small molecules that block angiogenesis—such as the ones that are used in first-line renal cancer, combined with anti–PD-1 or anti–PD-L1 antibodies, such as pembrolizumab or avelumab—has activity, has become the standard therapy for these patients. We know, for example, that combining bevacizumab and atezolizumab is another PD-L1 antibody that is becoming the first-line potential preferred therapy for hepatocellular carcinoma. There is a strong rationale combining either anti-VEGF monoclonal antibodies or tyrosine kinase antiangiogenic small molecules with PD-1 or PD-L1 antibodies in metastatic colorectal cancer. With a report last year of interesting data in MSS patients with refractory disease of combining regorafenib and nivolumab. At the current annual congress at ASCO some data have been presented in an abstract and then in a presentation, like the combination of regorafenib with a PD-L1 antibody, avelumab. The rationale behind these combinations is that there’s a broad spectrum of action of regorafenib. It blocks several tyrosine kinases that are important for endothelial cells and several cells that are involved within the microenvironment of the tumor, who in some way interact with the T-effector cells. This inhibition could increase the activity of PD-1 or PD-L1 antibodies. I hope we will have more data in the near future because, unfortunately, the bottom line—especially after the KEYNOTE-177 randomized phase 3 trial—is that we know that for MSI-high patients, pembrolizumab, a PD-1 antibody, is very effective. However, these patients are only 5% of metastatic colorectal cancer patients. What can we offer them in terms of immunotherapy to the other 95%? This is a very important topic, in which the combination with other molecular-targeted agents—such as EGFR inhibitors in select patient populations with RAS/RAF wild type or with broad spectrum antiangiogenic drugs. In terms of regorafenib, it is very interesting and is worth to be addressed in new studies.

Transcript Edited for Clarity