Tweet Chat Recap: Nivolumab Plus Ipilimumab Best Choice for Second-Line Metastatic CRC

In an interview with Targeted Oncology following a tweet chat, Mark Lewis, MD, discussed the key takeaways from the discussion and highlighted both the role of immunotherapy in metastatic colorectal cancer and the management of toxicities associated with chemoimmunotherapy regimens.

Targeted Oncology was joined by Mark A. Lewis, MD, a medical oncologist and director of gastrointestinal oncology at Intermountain Medical Oncology-IMC, for a discussion of a 68-year-old man with newly diagnosed stage IV colorectal cancer (CRC) in a recent tweet chat. In this case scenario, the patient presented with a tender abdomen on deep palpation in the right lower quadrant. The patient was initially treated with the FOLFOX regimen (oxaliplatin, fluorouracil, and folinic acid [leucovorin]), in combination with bevacizumab (Avastin).

In a Twitter poll ahead of the discussion, Targeted Oncology followers shared their thoughts on what might be the next best line of therapy for this patient. The majority of followers (42.1%) voted for the immunotherapy combination of nivolumab (Opdivo) plus ipilimumab (Yervoy), while many other followers (36.8%) voted for pembrolizumab (Keytruda) as monotherapy. Additionally, some people voted for a different chemotherapy agent (10.5%) or another form of therapy (10.5%).

The combination of nivolumab and ipilimumab was an option supported by data from the open-label, multicenter, phase 2 CheckMate 142 clinical trial (NCT02060188). In the study, frontline nivolumab/ipilimumab was administered to patients with microsatellite instability–high and mismatch repair deficient metastatic CRC. The combination achieved a 64% response rate, according to updated results presented at the 2020 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (ASCO GI), as well as a complete response rate of 18%. CheckMate 142 led to the FDA approval of nivolumab plus ipilimumab in this patient population.

In regard to the 36.8% of poll voters who would select pembrolizumab as the next line of therapy for the patient, Lewis noted that data does support its use for such a patient, but he would follow the recommended dosing schedule for the agent.

In an interview with Targeted Oncology following the tweet chat, Lewis discussed the key takeaways from the discussion and highlighted both the role of immunotherapy in metastatic CRC and the management of toxicities associated with chemoimmunotherapy regimens.

TARGETED ONCOLOGY: What was your first impression of this patient case?

Lewis: My first impression was that this patient struck a chord with me as being typical for my practice. The age of this patient is 68. That is the median age of patients with metastatic CRC in my clinic, which is exclusively devoted to GI oncology. Even her upfront treatment, I think, was consistent with not just my tendencies, but even national trends.

TARGETED ONCOLOGY: What was your reaction to seeing that the majority of the poll votes were in favor of using nivolumab plus ipilimumab for this patient?

Lewis: I wasn't surprised, I think that the ASCO GI meeting this year, and in fact, for many years now has been demonstrating the role of immunotherapy in the management of patients like this one. When you have a mismatch repair defect, or arguably any target for immunotherapy candidacy, that's an opportunity not to be missed. I was not surprised that my colleagues skewed towards immunotherapy and particularly were interested in the combination of nivolumab and ipilimumab.

Typically, as oncologists, we like to see high response rates, even though it's not necessarily the end point that matters most for our patients. If you're dealing with a patient that has metastasis in the liver, that organ matters a lot, and you have to preserve the liver at almost any cost. In this case, maximizing response rate makes a lot of sense. Also, the data supporting the combination of nivolumab and ipilimumab are arguably stronger than the data for pembrolizumab.

TARGETED ONCOLOGY: During the tweet chat, you highlighted the EPOC trial. Can you give a key takeaway from the study and its relation to the patient case discussed?

Lewis: The EPOC trial is a study that has caused some pause in the GI medical oncology community. To give some history here, in the last 15 years, we've come to realize that not all stage IV disease is created equal. Even near the beginning of my training, if I saw a patient with even a solidarity liver metastases, I would think of them in the same manner as someone whose liver was diffusely involved in both lobes. Thankfully, through advances like immunotherapy, chemotherapy, surgical therapy, and interventional radiology, we are now able to cure some patients with liver metastases. However, the EPOC study introduced some concern that if you use upfront cetuximab (Erbitux) before you take the patient to liver surgery, you might worsen their survival.

During the tweet chat, there was some dialogue about EPOC as being one of those studies that is troubling because we can't explain it. Not every patient is even a candidate for EGFR-directed therapy, and in fact, patients with right-sided tumors rarely are. So that was a troubling finding from EPOC and it's one that our field has yet to fully reconcile. I'm very curious to hear others' comments on that.

TARGETED ONCOLOGY: You also referenced CheckMate 142 and KEYNOTE-177. Can you discuss these trial data and their relevance to the patient case discussed during the tweet chat?

Lewis: Going into this tweet chat, I anticipated that it would be CheckMate 142 up against KEYNOTE-177. It's a nice problem to have that we have these sort of dueling immunotherapy studies because the more options patients have, the better.

The CheckMate 142 trial was very interesting. It gave us data both on nivolumab alone and nivolumab plus ipilimumab. There's no doubt that you do get a higher response rate of roughly 55% by combining the 2 agents. However, we also know that ipilimumab is more toxic than nivolumab. It is an anti–CTLA-4 antibody and, as a class, they tend to be a little trickier in terms of autoimmunity in anti–PD-1 or PD-L1. One of the comments I made in the discussion was there's a real sort of balancing act as an oncologist in a conversation with the patient about the trade-off between increased response rate and a potential increase in toxicity. It has to be determined on a case-by-case basis.

I feel comfortable with nivolumab alone because that was part of the CheckMate 142 study. Michael Overman, MD, one of my former colleagues at The University of Texas MD Anderson Cancer Center, has presented those data for several years now. Another investigator, Heinz-Josef Lenz, MD, pointed out that it comes down to how you dose nivolumab, and I completely agree that you should give ipilimumab every 6 weeks, even though the nivolumab has been given more often. That seems to allow you to balance out those 2 agents.

TARGETED ONCOLOGY: Based on the limited data this are available, what would be your recommendation for sequencing therapies for this patient?

LewisI think it's still an individualized decision. The thing that gave me pause and that I mentioned during the tweet chat is that if you look at KEYNOTE-177, there's a very interesting crossing of the curves between pembrolizumab and chemotherapy. There was an initial plunge in the pembrolizumab arm and that tells us that not every patient is going to be appropriate for immunotherapy upfront. There are some people who still really need cytotoxic debulking with chemotherapy before it's appropriate to switch them to immunotherapy. There's a Gestalt here because typically you have a patient who has very bulky liver metastases. As an oncologist, I worry that if I can't get almost immediate shrinkage, that it's going to lead to liver failure and loss of life. The judgment call is on each individual oncologist. 

On the other side of the coin, I will say that there's only so long you can use oxaliplatin-based chemotherapy for before the patient runs into potentially crippling neuropathy. Dr. Axel Grothey at the Mayo Clinic actually taught me to respect the potentially irreversible impact of oxide platinum. We know that typically, patients can't receive 12 full-dose cycles of that drug without experiencing at least some neurotoxicity. That gives me pause when I think about patients who might otherwise be on chemotherapy. The proper sequence for many patients might actually be chemotherapy first for about 8 cycles. Then, if they're candidates for immunotherapy, they can be switched. Grothey, however, argued quite persuasively in the New England Journal of Medicine recently that immunotherapy drugs hold the promise of potentially sparing our patients from chemotherapy altogether. Again, that's a statement that not everybody agrees with. But Grothey and other key opinion leaders are really pushing for us to be thoughtful about immunotherapy and equally thoughtful about the toxicity of chemotherapy.

TARGETED ONCOLOGY: On the topic of toxicities, can you discuss the GI toxicities that can come up in a patient like this? How would you collaborate across disciplines to treat the patient?

Lewis: For many years in oncology, we've had drugs, particularly chemotherapy agents that cause significant diarrhea. The most common example of GI oncology today has been irinotecan, which is one of the backbones of chemotherapy in metastatic CRC. For many years, we've been used to managing diarrhea that was essentially caused by these drugs that sped up the gut and had a cholinergic effect. Oncologists, gastroenterologists, and emergency room physicians all became facile with managing them. But then we started using immunotherapy and our patients would come in with diarrhea and it is a completely different beast.

If you just give anti-motility agents and try to slow things down, you may be drastically under treating these people because what we worry about is missing autoimmune colitis. The main risk of all immunotherapy is turning on the body's T cells and having them attack native tissue. We know that with immunotherapy, there is a nonzero risk of colitis. Often people have already had gut surgery, so if they’re experiencing a metastatic recurrence of CRC, you probably already have a shorter gut to start with. The education is not just among the doctors, it's also telling the patients that diarrhea is something they need to alert their oncologist about.

Oftentimes, we have to intervene with steroids, and sometimes even more powerful agents like infliximab (Remicade), to slow down colitis. We have to be very judicious in how we do that. There's been a debate for many years now about whether we are lessening the impact of immunotherapy by doing these things, which, of course, is something else we don't want to do. Overall, immunotherapy is wonderful. It is not without its risks and adverse events. I think we've been learning as we go how best to manage those toxicities and specifically colitis in this population.

TARGETED ONCOLOGY: What is your key takeaway from the tweet chat?

Lewis: What’s most fascinating is how people answered the survey. I think you can still see there's no consensus on the best approach. I understand that because this is a field where the evidence base is evolving. Immunotherapy, of course, is an umbrella term that encompasses many different agents with different toxicity profiles. Most of us now have been using them for several years in practice. I first started using nivolumab in 2011. It’s exciting to be in the infancy of this.

On the other hand, you want things to progress quickly so that it can benefit our patients. The other reason for the heterogeneity of decision making is that we're still in the infant stages of understanding the microbiome. There was some exciting work at ASCO GI this year, suggesting that the microbiome [correlates with] response to immunotherapy. As oncologists, I think we're still unsure about how to do that but it’s going to be a key biomarker in the future.


Lenz HJ, Lonardi S, Zagonel V, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/dna mismatch repair deficient metastatic colorectal cancer: clinical update. J Clin Oncol. 2020;38(suppl 4):11. doi:10.1200/JCO.2020.38.4_suppl.11