Colorectal Cancer Coverage from Every Angle

Nivolumab (Opdivo®) Plus Ipilimumab (Yervoy®) (Colorectal Cancer)

Posted: Monday, April 1, 2019

Dual Checkpoint Inhibition for an Immunologically ‘Hot’ Tumor

Roughly 15% of all colorectal cancers and 5% of metastatic colorectal cancers show a high level of microsatellite instability (MSI-H) or a deficiency of DNA mismatch repair (dMMR).1–4 Among other features, these tumors have dense lymphocyte infiltration and abundant neoantigens, making immune checkpoint inhibition an attractive treatment strategy.5

The phase II CheckMate 142 trial showed the efficacy of the combination of an antibody to programmed cell death protein 1 (PD-1)—nivolumab—and an antibody to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)—ipilimumab—among patients with metastatic colorectal cancer that had progressed during or following treatment with a fluoropyrimidine and oxaliplatin or irinotecan.6 The overall response rate was 55% at a median follow-up of 13.4 months, with good safety and tolerability. The benefit was durable, with an overall response rate of 58% at a median follow-up of 25.4 months.7

On the basis of CheckMate 142 data, the U.S. FDA granted accelerated approval to the nivolumab and ipilimumab combination for treatment of adult and pediatric patients 12 years and older with MSI-H or dMMR metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.8 (Nivolumab is also approved as single-agent therapy in this setting; see related JNCCN 360 Spotlight.) The combination is listed among second-line therapy options for this patient population in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).3,4

Patient Selection

“The NCCN Guidelines recommend ipilimumab nivolumab as second- or subsequent-line therapy for patients with MSI-H tumors, whereas the FDA approval specifies that it’s appropriate for patients who have received a fluoropyridine, oxaliplatin, and irinotecan. That could be a second-line situation, but a lot of times, it’s third line,” noted Michael J. Overman, MD, Professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. “But I’m not sure that makes much difference.”

Within the MSI-H/dMMR population, there are not yet any additional biomarkers to identify patients more likely to have a response. “But the good news is that the majority of patients with MSI-H tumors do benefit, so we know that’s a pretty good biomarker to start with,” he said.

Because the FDA label does not specify how MSI-H/dMMR should be determined, clinics can choose among several standard-of-care methods.9 One method is immunohistochemical (IHC) assessment for loss of mismatch repair proteins. Another is assessment for altered length of microsatellites, either by comparing a classic set of five microsatellites or by using a next-generation sequencing panel that assesses many microsatellites.

“All of those approaches for colorectal cancer are equivalent. From our view, how you determine MSI-H/dMMR is not such a critical issue,” Dr. Overman commented. “We tend to use IHC because it’s fairly easy to do, relatively low cost, and a very good, clean test. dMMR is evident as complete loss of staining on IHC—there is no gradation—and every slide has some normal tissue on it, so you have your positive control.”

Biomarkers for increased toxicity are lacking. Studies in colorectal cancer to date have excluded patients with autoimmune conditions, so it is unclear whether using the combination in this population would increase the risk for a flare or the frequency or severity of immune-related adverse effects. “In melanoma, where they have used immunotherapy for a lot longer, they have a lot of experience treating people with autoimmune conditions. There is a higher risk of some adverse events, but it often is still an option for patients,” he said. “However, there has to be a discussion of risk/benefit between the patient and doctor.”

Availability of new therapeutic options specifically for metastatic MSI-H/dMMR disease underscores the importance of testing.10 “If patients have had a resection and then experience a recurrence, the standard now is to check the microsatellite stability of the tumor. If the tumor meets the criteria for immunotherapy, there is great potential for response to the combination in MSI-H disease,” explained Edith Brutcher, NP, ANP-BC, MSN, AOCNP, an oncology nurse practitioner at Emory Winship Cancer Institute, Atlanta.

Patient Education

When ipilimumab and nivolumab are used together, patient education, particularly regarding toxicities, is key, according to Dr. Overman, who has more than 3 years of experience with this combination in trials and in practice. “Toxicities from these immunotherapies are very different from those of standard chemotherapy. They often start as minor symptoms but just get more and more severe, in contrast to chemotherapy toxicities, which patients often just manage on their own with guidance and supportive measures,” he elaborated. “For the immune-related side effects, we need the patient to let us know what’s going on so that we have the opportunity to intervene if necessary. It is a different mind set not just for the provider, but also for the patient.”

“We discuss with patients the fact that immunotherapy is different from chemotherapy because they are most familiar with the general concerns of chemotherapy,” concurred Ms. Brutcher, who has 2 years of experience with the nivolumab/ipilimumab combination in both trials and practice. “We explain how it works with the immune system. And then we explain that with the keyed up immune system, the treatment can affect other systems in the body, which could result in immune side effects.”

Schedule and Doses

The standard schedule and doses for combination therapy are those used in the CheckMate 142 trial for patients with chemotherapy-refractory colorectal cancer: nivolumab at 3 mg/kg followed immediately by ipilimumab at 1 mg/kg on the same day, every 3 weeks for 4 doses, with maintenance nivolumab monotherapy at 3 mg/kg or 240 mg every 2 weeks thereafter. However, a subsequent cohort of patients with MSI-H/dMMR metastatic colorectal cancer in the trial were treated in the first-line setting with a somewhat different schedule and doses: nivolumab at 3 mg/kg every 2 weeks and ipilimumab given at the same dose but half as frequently, 1 mg/kg every 6 weeks.11 In addition, the combination was administered continuously and not stopped after four doses. [Editor’s Note: Tthis dosing is off-label and is not included in the NCCN Guidelines.]

“This new regimen was explored because it’s been found to be better tolerated in other tumor types. One of the biggest points with the nivolumab/ipilimumab combination is that there are different ways of giving the ipilimumab, which affect the toxicity,” Dr. Overman explained. “The patients in that first-line cohort actually received more ipilimumab than the patients in the refractory cohort—about twice as much at the time the initial results were reported. But that schedule was markedly better tolerated if you do cross-arm comparisons.”

One of the biggest points with the nivolumab/ipilimumab combination is that there are different ways of giving the ipilimumab, which affect the toxicity

For example, the rate of serious treatment-related adverse events was 23% in the original, refractory cohort, compared with 13% in the first-line cohort; meanwhile, efficacy appeared similar. “There are some caveats with cross-arm comparisons, but it is encouraging that we could eventually give this combination slightly differently, that is, using this first-line approach, and have better tolerability,” Dr. Overman added.

Managing Toxicities

In the CheckMate 142 trial, the most common adverse events of any grade with combination nivolumab and ipilimumab, seen in at least 20% of patients, were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.12,13 The main grade 3 or 4 adverse events were fatigue (6%), rash (4.2%), diarrhea (3.4%), and musculoskeletal pain (3.4%).

However, the combination also carries the risk of immune-mediated adverse effects, some of which may become severe enough to require withholding or discontinuing ipilimumab alone or both drugs, as well as corticosteroid treatment. These immune-related adverse effects include immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (eg, hypophysitis, adrenal insufficiency, and hypothyroidism and hyperthyroidism), and skin reactions.

“In general, we’ve been able to manage patients well through this therapy, though they do have a higher rate of immune-related adverse events with the combination as compared with nivolumab alone,” Dr. Overman reported. “So the combination does require a bit more attention to patient symptoms.”

As patients with metastatic colorectal cancer on combination therapy may experience diverse symptoms related to the disease and its treatment, the first step is discerning whether they are immune related. “A key clue to an immune-related process when patients are on this therapy is that, generally, the symptom will worsen over time,” he noted. “Then it is important to assess whether you think it is more of an ipilimumab side effect versus a nivolumab side effect. Ipilimumab tends to have a slightly different spectrum of side effects—more colitis, more hepatitis, more gastrointestinal toxicities. If you think it’s solely ipilimumab driven, there is always the option of dropping ipilimumab and continuing with nivolumab alone.”

“Catching immune side effects early is critical because they can progress fairly rapidly, even becoming severe and life-threatening,” Dr. Overman stressed. It is therefore essential that patients communicate about symptoms with the clinical team. In turn, the clinical team should provide close monitoring and follow-up, which may entail tracking symptom progression via phone calls, seeing the patient more frequently, and even admitting the patient for a workup.

As a general rule, the threshold for starting corticosteroids is a grade 3 toxicity. “From my experience, if you have a good sense that a symptom is due to an immune toxicity, starting steroids sooner rather than later is wise, as these toxicities can get severe fairly quickly,” Dr. Overman advised. “Then, when it’s time to stop the steroids, they should be slowly tapered: the recommendation is to taper over 4 weeks or even 6 weeks. Rapid steroid tapers tend to result in flares of the condition.” Providers can find comprehensive information on managing specific immune-related toxicities in a recently published article in the Journal of Clinical Oncology14 and in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities.15

“There was a concern about the potential for increased colitis in the colorectal cancer patient population with the use of combination immunotherapy,” Ms. Brutcher noted, as both nivolumab and ipilimumab can cause this condition, and patients with metastatic disease can have an elevated baseline risk for various other reasons. “We worried that giving the combination to these patients could result in unacceptable gastrointestinal toxicity, but we haven’t found the incidence to be higher.”

It really comes down to education and clear communication among the patients, their families, and the clinical team

“We don’t have a way to reduce side effects with this combination, so the goal is to catch them early and intervene early, to prevent them from becoming high-grade side effects,” she said. Her clinic similarly monitors patients on nivolumab/ipilimumab closely. “It really comes down to education and clear communication among the patients, their families, and the clinical team,” she maintained.

Patients and their caregivers are instructed to notify the clinical team of any changes without hesitation. “I tell patients, if you have any doubt about anything, call. I’d rather you call than not call. It may increase our volumes, but it also increases our safety,” Ms. Brutcher said.

Triage phone nurses are trained to collect detailed information, review past notes in patients’ medical records, and be alert for red flags. “We stress that they need to understand what treatment the patient is on, when they last received it, and when the symptoms began,” she commented. “It’s imperative to have a good telephone interview process, effective triage, and well-educated nurses and staff.”

“There are so many possible etiologies of diarrhea to consider in patients with colorectal cancer—everything from malabsorption if they have had surgery, to chemotherapy side effects, immunotherapy side effects, and infections, including Clostridium difficile infection. But the triage phone nurses especially need to know not to treat patients receiving immunotherapy with antidiarrheal agents (eg, diphenoxylate and atropine; loperamide), as you would for a patient on standard chemotherapy, because diarrhea can indicate colitis,” Ms. Brutcher commented.

Treatment Holds and Discontinuations

Based on Dr. Overman’s experience, the most common adverse effects of combination nivolumab/ipilimumab that require holding therapy and/or aggressive steroid treatment  have been pneumonitis, hepatitis, colitis, and hypophysitis.

“It’s often frustrating to have to hold a therapy that’s working in a patient. But our experience has been that even when patients have side effects and you hold the therapy, there is still a benefit from the therapy if it’s working,” Dr. Overman commented. “So we should probably have less concern over holds and long steroid tapers when they need to be done.”

In her clinic, the side effects most commonly triggering treatment holds have been skin reactions and elevations of liver enzymes, according to Ms. Brutcher. The approach to restarting therapy after a hold is individualized.

“In our population of patients with colorectal cancer, we have not had to hold treatment frequently,” she reported. “But as the numbers of patients treated increases, we are going to encounter holds and stops more often, as we have seen in other tumor types, such as in patients with melanoma.”

Multidisciplinary Care

“It’s helpful to include experts from other disciplines on your team with whom you can discuss challenging cases,” Dr. Overman commented. “Patients can develop severe immunotherapy-related conditions that oncologists haven’t necessarily managed much in practice. So being able to consult with specialists in those areas is a real benefit.”

At least three specialties are key, he explained. A gastroenterologist can provide a rapid endoscopic evaluation to determine whether diarrhea and/or colitis is due to an immune process. A dermatologist can treat more serious skin toxicity, such as Stevens-Johnson syndrome. And an endocrinologist can be invaluable in troubleshooting possible pituitary dysfunction related to immunotherapy. “If you think the patient has a pituitary dysfunction, you order a host of pituitary hormone tests. It’s extremely helpful to have an endocrinologist assist because these tests can be confusing and a bit challenging to interpret,” he acknowledged.

Ms. Brutcher’s clinic draws on these same specialists and even has a dedicated dermatologist for oncology. “We are also lucky to have clinical pharmacists, and pharmacy is involved heavily with our patient care,” she added.

Gray Areas in Need of More Data

More data will be required to address several gray areas regarding immunotherapy for MSI-H/dMMR metastatic colorectal cancer. Given that both nivolumab monotherapy and nivolumab/ipilimumab combination therapy are approved in the same treatment space, a key question is whether patients need the combination or can get by with monotherapy.

“We don’t really know the answer to that question because CheckMate-142 wasn’t a randomized trial,” Dr. Overman noted. “That said, it appears the combination works a little better. Overall, it works very well, and its benefit appears to be durable. We believe we are probably even curing a fraction of patients with MSI-H metastatic colorectal cancer when we use this combination therapy. From my view, a combination that has a little bit more toxicity but allows us to increase the potential for cure… that’s actually a reasonable tradeoff to discuss with the patient.” 

Another important question is whether patients can be given nivolumab first and then go on to receive combination therapy. Would they derive the same benefit as if they had started with the combination initially? “One might think, if initial monotherapy doesn’t work, then I’ll do combination therapy and get the same benefit. But if monotherapy works, the patient didn’t need that other drug and will have fewer side effects,” Dr. Overman elaborated. “Unfortunately, there have been no studies in MSI-H patients to know how combination therapy works after disease progression on an anti–PD-1 agent. In melanoma, it’s pretty clear that ipilimumab can work after patients experience disease progression on nivolumab or pembrolizumab, another anti–PD-1 agent. With time, we’ll get data in MSI-H colorectal cancer.”

Finally, there is uncertainty about cost-effectiveness. At present, analyses suggest the combination of nivolumab and ipilimumab for MSI-H/dMMR metastatic colorectal cancer is not cost-effective, with an incremental cost-effectiveness ratio of approximately $160,000 compared with chemotherapy in the third-line setting and combined chemotherapy–targeted therapy in the first-line setting.16 However,it is possible that changes in drug pricing, the regimen, or both may favorably shift that calculus.

Looking Ahead

Our hope is that we can expand the treatable population by discovering how to induce responses in patients outside of the limited population of patients with MSI-H tumors

Future prospects for immunotherapy in MSI-H/dMMR colorectal cancer are promising, according to Dr. Overman. Longer-term follow-up of patients enrolled in the CheckMate 142 trial, coupled with emerging clinical experience, will help clarify what already appears to be a favorable risk-benefit profile of combination nivolumab and ipilimumab in patients who have previously received chemotherapy.

“The first-line data with the combination look exciting at an early time point, so one possibility is moving this combination earlier in therapy,” Dr. Overman noted. “Also, different schedules will likely become more common. Ongoing studies in other tumor types are helping to identify better, well-tolerated combination regimens, with further optimization of dose and schedule.”

“Our hope is that we can expand the treatable population by discovering how to induce responses in patients outside of the limited population of patients with MSI-H tumors,” Ms. Brutcher commented. “We are really happy with where we are, but we are definitely looking to increase the treatable population.” 



Michael J. Overman, MD, has received research funding from and is a consultant to Bristol-Myers Squibb.

Edith Brutcher, NP, ANP-BC, MSN, AOCNP, reported no conflicts of interest.



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