Optimal Treatment for Advanced Colon and Rectal Cancers : Episode 14

Efficacy and Safety of Immunotherapy for mCRC

November 21, 2018

Video

Transcript: Johanna C. Bendell, MD: So, thinking about immunotherapy, the big buzzword, right? Let’s talk about good news and bad news. Why don’t we start with the good news for the patients with microsatellite instability-high [MSI-high] colorectal cancer, [and] recent FDA approval as well. Heinz, you’re presenting data on NIVO/IPI [nivolumab/ipilimumab].

Heinz-Josef Lenz, MD, FACP: So the data for MSI-high; the CheckMate-142 data presented multi-cohorts. One of them was the refractory. Michael Overman [MD] presented it. It’s now in The Lancet Oncology showing [a] response rate over 55% and incredible duration of response, leading to the approval in [the] MSI refractory patient population. So the question is, if you reach so much in refractory, why don’t we move it to earlier lines? So we treated 45 patients [with] MSI, newly metastatic disease.

Now, you need to know that MSI-high tumors are the ones with the bad prognosis. These are the ones with the PFS [progression-free survival] of 8 months and survival of 15 to 20 months, depending where you look. So these are not doing well. Now, we saw [a] response rate of 60%, [7% went into complete remission]. Now, the worrisome [thing] when you do NIVO and IPI is toxicity, and the toxicity mainly comes from IPI. So, in the refractory patient population, they got 1 mg every 3 weeks; in the first-line every 6 weeks. [There was a] very big difference because the toxicity in the refractory grade 3 and 4 was 32%, and in first-line it [was] 16%, lower than the NIVO [monotherapy], [so] very well tolerated. Now, you can imagine the response rate, the duration of response is not reached. I think 80% are still on treatment. PFS is not reached. Overall survival is not reached. We only know at 12 months, progression-free survival was 73% and overall survival 84%. It will outpace all the data we have seen before with very good toxicity. So this data set will potentially ask the question, should we use it in first-line, and is it enough data to get approval? That’s not in my hands. I would clinically use it tomorrow.

Johanna C. Bendell, MD: Because, technically, the approvals right now for NIVO/IPI, NIVO and PEMBRO [pembrolizumab] for MSI colon cancer are in the refractory, [and] the third- and above-line setting. And that’s always been the question, right? If we’ve got such great response rates, great survivals, why can’t we use it earlier? So here’s my question, Dirk. Would you use a) NIVO/IPI, b) PEMBRO, c) NIVO, and which line would you do for your MSI-high patients?

Dirk Arnold, MD, PhD: We’re eagerly waiting for data from randomized trials, [which] will come hopefully very soon, asking exactly this question. They will see, we’re super sure that this will be better, this will be the more successful treatment strategy. The question is only how good is it really. So what is the overall survival you see there? What is the progression-free survival we see? Are we also inducing responses [that] may then lead or open the door to surgery, or resection, or ablation of metastases, which you practically have implemented in your therapeutic algorithm? So these questions are still open. I would say let’s wait. My personal take [is] let’s wait for this data. It looks promising. I’m sure that we have a super successful treatment, however, a combination chemotherapy plus monoclonal antibodies are not bad either.

Johanna C. Bendell, MD: So you would save it now [for] refractory as it’s approved?

Dirk Arnold, MD, PhD: Well, I would like to see. Before I see data from [a] randomized trial in first-line, I would be saving this for refractory patients.

Johanna C. Bendell, MD: And do you like doublet or singlet?

Dirk Arnold, MD, PhD: Well, the doublet data are really amazing, so looking forward to seeing them tomorrow being presented. And I think it makes sense to think about combinations. So I do believe that combinations are the way to move forward, these immuno combinations, but we have to see the data.

Johanna C. Bendell, MD: Yeah. The CheckMate-142 was very impressive. What was it, 86% 1-year survival with the doublet?

Heinz-Josef Lenz, MD, FACP: Yes. That’s in refractory.

Dirk Arnold, MD, PhD: In refractory.

Heinz-Josef Lenz, MD, FACP: So can you imagine what will happen. And I think I have to say because obviously we are actively participating, we had patients who were on this trial, no [adverse] effects whatsoever, dry skin, who the tumors didn’t shrink anymore, they didn’t shrink anymore. PET [Positron emission tomography] was negative. I took out this big liver lesion which was only a PR [partial response]; took out the tumor lesion, complete pathologic response. I have never seen that. I was sweating in the surgery. I said, “You have to call me, you have to call me [with] what you find.” So the second patient who had the same, I went after it, too, but it was in situ cell somewhere, a big tumor.

Johanna C. Bendell, MD: We’ve seen that in lung cancer, too, where you resect and there’s nothing there.

Heinz-Josef Lenz, MD, FACP: Exactly. So I think there is a complete…we know the calcification, but with immuno, it’s like more fibrotic, you don’t see it, you don’t know what’s going on, you’re breathing hard thinking what should you do.

Dirk Arnold, MD, PhD: But we see this in [chemotherapy] in 50% to 60%, even more [percentage] of patients, the tumors shrink, and we have to see in how many patients we will see this also. And so many candidates for resection and ablation in first-line, 30% plus, etcetera. So, therefore, we really have to see whether it will work, but I’m not sure how we can implement this in therapeutic algorithms. Maybe liver-only patients are candidates for chemotherapy, antibodies, [while] widespread disease [patients] are candidates for immunotherapy, but that’s speculation.

Heinz-Josef Lenz, MD, FACP: We have to really remember the MSI-high do very poorly with [chemotherapy]. Remember, [for] the CMS I [consensus molecular subtype 1] classification, the response rates are about 30% to 40%. PFS is 8 months, survival is 20 months in these trials. So you cannot compare to the best outcome, you know. At the beginning I thought 60%, is actually more than double what we see, and the survival will be following this. We don’t have it, but that’s a good sign to have.

Zev A. Wainberg, MD: It’s amazing because the data [are] so strong with MSI with immunotherapy, both combination and single agent checkpoint inhibitors, that we should be starting to ask the question of how long these patients actually need to be on these drugs. Because one thing that I think we’re facing, particularly in the refractory group, [is] where we’re seeing these patients are on these drugs for two years, and they have amazing responses. But the question is with an immunotherapy drug, it’s not like chemotherapy. Do they need to stay on it or has the immune system then sufficiently engaged at that point? And they’re looking at this right now in lung cancer. And MSI-high tumors are even more sensitive to checkpoint inhibitors than even the highest PD-L1 [programmed death-ligand 1] non—small cell lung cancer. So we should probably be starting to think about those kind of things. Is two years sufficient, for example, of NIVO/IPI? Can we stop at that point? [That’s what] makes it a whole new world of clinical trial design, actually, for that group.

Heinz-Josef Lenz, MD, FACP: I have this refractory patient, after 2 years I stopped. Now, the reason I use 2 years is because of the data in other diseases, in melanoma. Then there was no evidence of disease after 2 years and they stopped; not one recurred yet.

Zev A. Wainberg, MD: And even if they do have evidence of disease, if they have minimal liver lesions, can you still stop?

Heinz-Josef Lenz, MD, FACP: We don’t know. We don’t know.

Transcript Edited for Clarity