Role of I/O Combination Therapies in mCRC

Heinz-Josef Lenz, MD, FACP: I have no doubt in MSI high immunotherapy is the most successful treatment. I think the question is not immunotherapy versus chemotherapy. The question is what immunotherapy do we choose? Right now we have 2 options: pembrolizumab or nivolumab-ipilimumab combination. I would never give nivolumab alone because of all the data. There is no side-by-side comparison, but the combination seems to be consistently better. When you choose ipilimumab at the right dosage, with 1 mg every 6 weeks, the toxicity is not different from nivolumab alone, so I’m very comfortable with a nivolumab-ipilimumab combination. The problem is that we don’t have the statistical powers, since comparisons are not done, to tell if the combination is better than pembrolizumab. Is it the same? Just looking at the data presented at ASCO this year, 30% progression of disease is the best response, with the first CT scan. It is a little worrisome because we don’t see that with nivolumab-ipilimumab, also recognizing that this is a much smaller study. But the 30% progression was seen in other later-lines of treatment with KEYNOTE-164. I think this gives us a lot of ideas to better understand what the best immunotherapy combination is for this patient combination.

Axel Grothey, MD: Turning a cold tumor into a hot tumor is the holy grail of developing immunotherapy right now, and this goes beyond the question of MSI high versus MSS. There are some data that we’ve seen over time across the landscape of solid tumors that sometimes combinations of checkpoint inhibitors, PD-1 and PD-L1 inhibitors, and chemotherapy can turn an otherwise cold tumor into a hotter tumor, likely by releasing neoantigens and tumor antigens in the environment. A combination of immunotherapy plus chemotherapy in PD-L1–low tumor it seems to be more effective than just immunotherapy alone.

Then we’ve learned that combination of immunotherapy, like checkpoint inhibitor combination, PD-1 antibodies plus CTL4 antibodies, ipilimumab-nivolumab, can be interesting and can potentially turn some of the colder tumors into hotter tumors. This is not the 1-size-fits-all treatment for all cancers. I do believe, from all the data we’ve seen, we need an additional modulation. It could be that different patients, even in 1 cancer type, need different approaches to activate the immune system. The idea right now is to really generate an immune profile of tumor before treatment, so you know what angle we need to use to turn these tumors from cold into hotter tumors, recognizable by the immune system. This could be very individualized treatment approach.

Heinz-Josef Lenz, MD, FACP: The way to move forward with immunotherapy in microsatellite stable tumors is speedy combination treatments. This could be with other immune system–targeting drugs, like OX40 agonists and many different ones. There is approved synergism between the anti-VEGF strategies and immune checkpoint. The data in HCC with bevacizumab and atezolizumab are amazing. It is approved in first-line, where is has the highest response rate. The anti-VEGF strategies with immune checkpoint makes a lot of sense. The reason is that anti-VEGF really modulates the polarization of the macrophages, which plays a significant role in the immune response pathway. VEGF is a part of an immune response through the macrophage’s polarization from M1 to M2. Here, I think there is a potential understanding that this combination may be very helpful. The most data we have are on regorafenib-nivolumab from Japan that showed a 36% response rate in this patient population. This is unheard of in refractory patients. What is even more exciting is when you look at the gastric cancer cohort, there is a 44% response rate. Of these patients, there are patients who had previously been treated with immune checkpoint inhibitors who responded to this combination. I think you can overcome resistance to immune checkpoint with regorafenib-nivolumab combinations, which gives us some clue that this may be a promising combination for patients who are usually not candidates for immunotherapies. We still need to learn who are the patients who benefit from this combination, because 1 of the discussion points coming out of regorafenib-nivolumab from Japan is that the patient selection in Japan may be a little different. Patients there have less tumor burden, maybe have fewer tumors involved in the liver and more in the lung. These are the patients who may benefit more. We are going to learn much more. There are many clinical trials going on with TKIs [tyrosine kinase inhibitors] of the VEGF pathway and immune checkpoints. Within the next year, I’m sure we’ll be learning much more the efficacy and hopefully also about which patients will benefit the most.

Transcript Edited for Clarity