IMblaze370 Regimen in MSS Tumors

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Fortunato Ciardiello, MD, PhD: Most colorectal cancer patients with disease have a microsatellite stable [MSS] tumor, and although there are differences in genetic alterations and in stromal interaction with the tumors, most of these tumors could not be receiving any immunotherapy because these are not effective at all. There has been an attempt to find if there is a way to reactivate the immune function totally by using a PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] monoclonal antibody and by activating the immune function in the tumor, a study was performed, and it was called the IMblaze370. That was a randomized phase II trial based on the very relevant, interesting mechanistic observation from the preclinical models and from early clinical trials. This study was evaluating the combination of a MEK inhibitor, cobimetinib. But it is now currently used in the treatment of BRAF-mutant metastatic melanoma patients in conjunction with BRAF inhibitors and cobimetinib in combination with a PD-L1 monoclonal antibody, that is atezolizumab, that is currently used in the treatment of metastatic lung cancer.

The rationale behind this combination was very strong, with compelling evidence coming from preclinical studies from early phase I data showing that MEK inhibition in the tumor cells—as well as in the stroma and in the immune component, which could contribute to block some inhibitors of immune response and cooperate with PD-L1 to reactivate the immune response in the tumor.

Actually, the early phase I study in about 23 patients gave very promising results, so investigators finally decided to do a randomized phase III trial in which patients were randomized to receive regorafenib, a standard arm in this chemotherapy-refractory third-line setting, versus 2 experimental arms. One was atezolizumab alone, and the second was the 1 that was thought to be the most active; therefore the combination was the MEK inhibitor, cobimetinib, and the PD-L1 inhibitor, atezolizumab. Unfortunately, the study result was negative. And in MSS patients, unfortunately, again it was shown that blocking PD-L1 or PD-1 is the same, or even trying to announce the efficacy of PD-L1 inhibitors by MEK inhibition, does not translate in a clinical benefit or in better efficacy. In fact, there was no difference in overall survival between the 3 arms.

Tanios Bekaii-Saab, MD: The world is shifting very aggressively into immune therapies, and understandably, we’ve seen some cancers move or agents move the needle very positively in many cancers like melanoma and lung cancer. We’re hearing the same story with triple-negative breast cancer, bladder cancer, and kidney cancer. So a lot of cancers are seeing what I call the immune therapy revolution, although we still have to learn quite a bit before we can call it a true revolution. In the other solid tumors, it’s been kind of challenging—specifically in colorectal cancer—to apply the immunotherapy agents to the large patient population.

For MSI-high patients, the microsatellite instability high, when those patients have a high tumor mutational burden and they’re a little bit more visible to the immune system, we found that the use of a PD-1 inhibitor, such as pembrolizumab or nivolumab, has a significant response, including some durable responses. In fact, for some patients, I think we cure them. And I don’t use that term loosely. We cure them with immune therapy. I’ve had patients 5-plus years after in complete response, and actually they had stopped the drug at 2 years. And so these 3 years—after 2 years on the drug—continue to be cancer-free. So they’re pretty amazing effects.

There are also data that suggest that if you add a CTLA4 inhibitor, ipilimumab to nivolumab, you may get a little higher of a response rate, although this was a nonrandomized setting. My preference remains to start with the PD-1 inhibitors first, and then you could consider what to do with the CTLA4 in those patients who don’t have the optimal response—not from the get-go, though.

We call these tumors hot because of the mutational burden. They tend to be inflamed, they tend to have all these tumor-infiltrating lymphocytes and other immune cells available in the microenvironment, which facilitates the activity of these PD-1 or PD-L1 inhibitors. The thought was—because this is only 4% of the patients—can we go after those other 96% of the patients and essentially inflame those tumors? And you throw in a PD-1 inhibitor, perhaps, or a PD-L1 inhibitor even, and perhaps we will see activity. There were preclinical data that suggested perhaps a MEK inhibitor could do that, cobimetinib and others as well. And so that was taken into the clinic. Phase Ib showed some hints of activity with cobimetinib and atezolizumab, and that created the need to build the phase III study IMblaze, which essentially had cobimetinib plus atezo [atezolizumab], atezo alone, and then regorafenib.

This study was negative for its primary endpoint, did not show any superiority for atezo-cobi [cobimetinib] or atezo versus regorafenib, with a progression-free survival. Actually, there were hints that we may be harming some patients with the combination, whereby regorafenib seems to pull the line predictably in a better direction than the 2. The survival on the study was north of 8 months for regorafenib, which is interesting. We’re seeing that survival, as we understand how to use regorafenib better and better, continue to improve because I suspect we know how to handle it better. We give it to the right patients, and we’re educating our patients better. We’re preempting certain things, and so patients are predictably staying on it longer. It’s interesting to see on that study that the survival looks a little bit more favorable than historical with regorafenib.

Unfortunately, the atezo plus cobi arm ended up being negative and really put a chill on developing, further, this strategy. We’re still very interested in taking some of these less hot tumors into becoming warm or hot enough to see benefit from PD-1 or PD-L1 inhibitors. The problem is, though, when we look at the curves from the atezolizumab and cobimetinib study, I don’t think there’s any hint that a group or subgroup of patients at this point in time may benefit more from this strategy. So the thought is we probably should continue improving on these strategies and maybe refine our patients better.

Axel Grothey, MD: Two years ago everyone was really excited about the combination of cobimetinib and atezolizumab in a later-line setting in patients with metastatic colorectal cancer because there were some intriguing data that patients who were not necessarily responsive to immunotherapy—the MSS tumors—responded to a combination of this MEK inhibitor plus a PD-L1 inhibitor, which by themselves really didn’t have any real activity in colorectal cancer. There were a few patients who responded, and then a phase III trial was initiated that compared this novel combination to regorafenib as a control arm.

The study failed and didn’t show any superiority of the combination, the exciting combination of immunotherapy plus cobimetinib over regorafenib. There are several lessons learned. First of all, regorafenib did better than people expected. It was not the easy-to-beat control arm. The overall survival data we saw with 8.5 months in the study were actually better than what we’ve seen in the initial study that got regorafenib to the market, potentially because we are selecting patients better, we know how to manage toxicities better now that the drug has been used for quite some time. So it’s intriguing to see the results with regorafenib now in more modern trials are better than what we expected from earlier trial results.

Secondly, you know it’s still not easy for me to see that you just combine a MEK inhibitor and immunotherapy, and all of a sudden it works in patients who were previously not responsive to immunotherapy. I think we really need to have good signal studies and clinical studies before we embark on another phase III study, and with an I/O [immuno-oncology] combination in these MSS colon cancers.

Transcript Edited for Clarity