Nivolumab (Opdivo®) - (Colorectal Cancer)
Posted: Tuesday, March 20, 2018
Nivolumab, a programmed death receptor-1 (PD-1) blocking antibody or immune checkpoint inhibitor has been approved for the treatment of patients with non–small cell lung cancer (NSCLC) and melanoma since 2014.1 Approval of immune checkpoint inhibitors for the treatment of other solid tumors, such as colorectal cancer, is much more recent. Nivolumab was approved for patients with metastatic colorectal cancer (mCRC) that has progressed after treatment with traditional chemotherapy regimens and whose tumors are microsatellite instability high (MSI-H) or mismatch repair–deficient (dMMR) in the summer of 2017.2 Despite a recent approval for this agent in the treatment of hepatocellular carcinoma,3 many oncologists who treat gastrointestinal (GI) cancers are less familiar with the use of these agents.
PD-L1 Versus MSI or dMMR?
One of the key differences about the use of nivolumab to treat patients with mCRC compared with patients with lung cancer or melanoma is eligibility. Whereas PD-L1 status is paramount in other tumor types, “In mCRC, expression of PD-L1 status may have little bearing,” stated Cathy Eng, MD, Professor, Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. To be eligible for treatment, patients with mCRC must have tumors that are MSI-H or dMMR. “Those with MSI-H tumors have an increased number of T-cell–infiltrating lymphocytes,4 which is why they are more responsive to an immunologic approach,” Dr. Eng explained.
At this time, nivolumab is approved for second- or subsequent-line treatment of mCRC, after disease progression on fluoropyrimidine, oxaliplatin, and irinotecan. However, Dr. Eng pointed out that a phase III trial of another immune checkpoint inhibitor in the first-line treatment of mCRC5 has recently opened and clinicians are encouraged to consider it for appropriate patients. Moreover, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon cancer6 and the NCCN Guidelines for Rectal Cancer7 note that nivolumab may be considered for initial therapy for patients who are not appropriate for intensive therapy, such as standard combination chemotherapy (eg, FOLFOX [fluorouracil, leucovorin, and oxaliplatin] or FOLFIRI [fluorouracil, leucovorin, and irinotecan]). In other words, patients whose performance status is not good and who would be intolerant of standard chemotherapy regimens (or who decline chemotherapy) may be considered for nivolumab in the first line. [Editor’s Note: Results of a nivolumab combination regimen were recently reported (and subsequently published) at the 2018 Gastrointestinal Cancers Symposium from a phase II nonrandomized cohort that was part of CheckMate 142.8,9 Researchers looked at the combination of nivolumab and ipilimumab for previously treated MSI-H mCRC. Encouraging results were reported for Checkmate 142, and longer follow-up of the monotherapy arm10 confirmed positive findings for response rates and disease control rates, as well as for progression-free survival and duration of responses with nivolumab and ipilimumab.]
Eligible Population Is Small
It is important to note that only about 5% of patients with mCRC are eligible for treatment with immune checkpoint inhibitors such as nivolumab. Dr. Eng described MSI in the overall population of patients with all stages of CRC: “There are two different types of MSI-H. One is associated with an inherited, familial condition, called Lynch syndrome.11 Patients with Lynch syndrome, who are usually young and comprise about 5% to 7% of the overall population with CRC, are at risk for other MSI-H–related noncolorectal tumors, notably uterine cancer.” Another 15% of the overall population with CRC, usually older patients, have a somatic mutation that results in hypermethylation of MLH1.11,12 These tumors are MSI-H and usually right-sided and poorly differentiated.12 The distinguishing factor is BRAF mutation. “If the BRAF mutation is not present,” she continued, “then the patient has Lynch syndrome.”
MSI-H: Beyond CRC
Dr. Eng urged GI cancer clinicians to make sure that all patients diagnosed with CRC have MSI or MMR testing, regardless of disease stage. Patients with MSI-H/dMMR tumors may have Lynch syndrome. A number of other cancers, such as small bowel tumors, stomach cancer, and endometrial and ovarian cancers, are also associated with Lynch syndrome and may be MSI-H/dMMR.14 Another immune checkpoint inhibitor, pembrolizumab, is approved for all MSI-H cancers (eg, small bowel or uterine cancer),15 whereas nivolumab is approved only in CRC. For patients who are diagnosed with Lynch syndrome, “there is an opportunity to prevent disease in family members or intervene early,” Dr. Eng pointed out. “If disease is discovered early, these patients may have a better prognosis and may not need adjuvant chemotherapy, especially in the stage II setting.16 And if disease progresses to stage IV, they may benefit significantly from immune checkpoint inhibitor therapy. Dr. Eng noted that patients with stage III MSI-H CRC are commonly offered standard FOLFOX as adjuvant therapy, but a trial of an immune checkpoint inhibitor in this setting was recently activated.17
Explaining Eligibility to Patients
Despite the fact that few patients with refractory mCRC are eligible for treatment with nivolumab due to the MSI status of their tumor, almost all patients ask about immunotherapy. “Public advertising campaigns have clearly worked, and patients ask about immunotherapy every day,” said Bridget O’Brien, DNP, APRN, FNP-BC, AOCNP, Director of the Family Nurse Practitioner DNP Program and Assistant Professor in the College of Nursing at Rush University in Chicago. “I explain that so far, results have been promising in small subsets of patients with GI cancers, such as in MSI-H mCRC,2 hepatocellular cancer,3 and even anal cancer,”18,19 she said. Dr. O’Brien, whose clinical practice is at Northwestern Medicine in the Robert H. Lurie Comprehensive Cancer Center, further explains that perhaps these drugs will be more widely applied in the future, but for “right now, we can only offer treatments that have been studied and shown to offer a benefit.”
Public advertising campaigns have clearly worked, and patients ask about immunotherapy every day.
Assessing the Full Clinical Picture
Dr. O’Brien emphasized the importance of assessing a patient’s total clinical situation whenever a second-line treatment is being considered. If the patient is eligible for nivolumab, “I don’t worry so much about whether the patient will be able to tolerate the regimen because most patients still have a pretty good performance status by the time they reach second-line treatment,” she said. “Rather, I will be thinking about specific pre-existing morbidities—elevated liver function tests, compromised kidney function, significant thyroid issues, uncontrolled diabetes—that might predispose them to some of the immune-related toxicities that could emerge with treatment.” For instance, a patient with lung disease might have a heightened risk for pneumonitis with nivolumab. “Fortunately, the risk for developing any of these toxicities is not high, but it makes sense to take a closer look when there’s already a pre-existing condition,” she explained.
Fortunately, the risk for developing any of these toxicities is not high, but it makes sense to take a closer look when there’s already a pre-existing condition.
Is it an Infusion Reaction?
Patients receive nivolumab in the infusion suite and are therefore monitored very closely. The nurses check in with them frequently and can act quickly if a patient seems to be having an infusion reaction. The infusion will be stopped and the patient will be checked by a physician or nurse practitioner. After an assessment, a decision is made about starting a supportive measure, such as adding corticosteroids, but sometimes “just giving the patient a break will be sufficient for symptoms to resolve. If there is a severe reaction, we probably will not rechallenge by continuing the infusion. But we are careful not to overreact unless symptoms truly warrant intervention,” Dr. O’Brien remarked. For instance, a patient may complain of mild chills, but “it’s winter in Chicago and the infusion suite can be cold! My point here is simply to take into account the complete clinical picture.”
Immune-Related Adverse Events: Individualizing Management
Most oncology clinicians are familiar with the concept of immune-related adverse events sometimes associated with immune checkpoint inhibitors.20,21 According to Dr. O’Brien, clinicians need to be aware of the symptoms of pneumonitis, colitis, hepatitis, even nephritis, and be aggressive about hospitalization and use of corticosteroids. With chemotherapy, “we might be less aggressive with management of symptoms like diarrhea. With immune checkpoint inhibitors, we want to be vigilant and should be more apt to intervene when early signs indicate a potential issue,” she cautioned.
Dr. Eng noted that hypothyroidism is seen commonly in patients with mCRC receiving nivolumab. “We frequently consult with endocrinologists who help us assess patients with thyroid issues.” She also said that in addition to rash or fatigue, clinicians should be mindful of more serious adverse events, such as colitis and pneumonitis. If a patient is hospitalized for either colitis or pneumonitis, for example, decisions about supportive treatment and subsequently about discontinuing or rechallenging with the immune checkpoint inhibitor should be individualized and made by the team, which includes specialists, such as the pulmonologist or gastroenterologist. “If the patient is hospitalized,” she explained, “the management decision may be very different compared with a decision about a patient being followed closely in the outpatient setting.”
Fatigue is commonly reported by patients with cancer of any type and is also associated with many anticancer therapies. “If a patient describes being more fatigued after starting on nivolumab, I first look for correctable factors, such as worsening anemia,” Dr. O’Brien said. What often gets missed when something vague like “fatigue” is noted are thyroid and/or glucose issues, which may develop with immunotherapy. “We want to make sure to thoroughly assess all of those types of clinical variables. It’s easy to attribute a generalized sense of fatigue to a new treatment, but we try to check into potentially correctable factors before jumping to that conclusion.”
Once the team is reasonably certain that an underlying medical cause of fatigue has not been missed, patients who feel fatigued are encouraged to maintain their activity levels and even to try to integrate a bit of exercise into their daily routines. Research suggests that exercise helps alleviate generalized fatigue, even and especially in patients with cancer.22 Dr. O’Brien suggests patients should start modestly: “I tell them ‘Take a 10-minute walk. Some days, you will be counting the minutes until those 10 minutes are done, whereas other days, you’ll keep going for 20 or even 30 minutes.’” Conversely, Dr. O’Brien emphasized that she gives patients “permission” to rest. Patients should be out of bed and in chairs as much as possible, but “we tell them, ‘You have to listen to your body. Some days, you will just need more rest and that’s fine. You should feel free to take naps or lie down, as needed.’”
Patient Education: An Ongoing Process
Nurses and other providers should do thorough patient education upfront, Dr. O’Brien urged, “to talk about ‘red flags’—eg, cough, shortness of breath, abdominal pain, symptoms of jaundice, uncontrolled diarrhea—and to proactively, aggressively monitor patients. We also need to encourage patients to call at any time of the day or night if they are concerned.” She reassures patients that the emergency phone number is always answered, and all interactions are logged. This way, “on Monday, the team knows what a patient called about on Saturday night and what advice and instructions were given.”
Patient education is an ongoing process. “There’s a lot to cover and patients cannot absorb everything at the first visit, particularly because the safety profile can be terrifying on paper!” Dr. O’Brien said. In addition to giving patients hard copy information to take home, she explains there are “questions to ask at every visit, such as, ‘Are you having any shortness of breath? Cough?’ We also cover issues that I want to hear about and what situations constitute emergencies.”
Something that cancer teams may not always think about is contraception. Some patients with mCRC, particularly those with Lynch syndrome, are still in their childbearing years. “We should be sure to talk with them about the need for contraception during treatment with nivolumab, as well as for up to 5 months afterward because of the potential for fetal harm,” Dr. O’Brien said.
Managing Adverse Events: Red Flags and Fine Lines
Nivolumab is given every 2 weeks, but patients should be followed up frequently, especially during the first few cycles. “We ask about diarrhea, for instance, at every visit,” Dr. O’Brien said, “but we want to hear from patients promptly if they develop diarrhea and then we can initiate an appropriate protocol.” Patients with mCRC may already have somewhat altered bowel function and are accustomed to tolerating mild diarrhea or constipation. Antidiarrheal medication may be tried and may be effective. “But if something starts to look more like a colitis situation, we need to consider corticosteroids, and those decisions are more likely to resolve well if dealt with promptly,” Dr. O’Brien said. The prescribing information spells out the recommended use of corticosteroids, based on the grade of the adverse event. For instance, 1 to 2 mg/kg/d of prednisone is used for grade 3 or 4 toxicities. Less-severe grades (ie, grade 2) may be treated with 0.5 to 1.0 mg/kg/d of prednisone. Corticosteroid treatment with appropriate tapering is often effective, but for patients who develop grade 4 diarrhea, hospitalization, intravenous fluids, and high-dose steroids may be necessary, as well as permanent discontinuation of nivolumab. The NCCN Guidelines21 also recommend second- or third-line immunosuppressive agents for steroid-refractory colitis.
Immunotherapy in mCRC: A Promising New Approach
“Those of us who have been involved with clinical trials have all seen promising, durable responses in these patients with MSI-H tumors when treated with an immune checkpoint inhibitor,” Dr. Eng noted. “The progression-free survival [PFS] for non–MSI-H patients when given standard therapy in the first-line setting is about 8 to 10 months; in the refractory setting, when disease has already progressed on treatment, PFS with standard therapies is shorter…perhaps 3 to 6 months. When a patient responds well to nivolumab, for instance, the PFS in this refractory setting might extend to longer than 1 year,” she reported.
Cathy Eng, MD, has disclosed that she has received research grants from Advaxis, Forty-Seven Inc, and Roche/Genentech. She serves on expert advisory panels for Sirtex, Bayer, Merck, and Roche. She has speaker agreements with Taiho, Roche/Genentech, and Celgene.
Bridget O’Brien, DNP, APRN, FNP-BC, AOCNP, has disclosed that she participates on speakers bureaus for Amgen and Novartis.
- Opdivo approval history. Drugs.com. Available at: https://www.drugs.com/history/opdivo.html. Accessed February 15, 2018.
- U.S. Food and Drug Administration. FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm569366.htm. Accessed February 15, 2018.
- U.S. Food and Drug Administration. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm. Accessed February 15, 2018.
- Phillips SM, Banerjea A, Feakins R, et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 2004;91:469–475.
- gov. Combination chemotherapy, bevacizumab, and/or atezolizumab in treating patients with deficient DNA mismatch repair metastatic colorectal cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02997228. Accessed February 24, 2018.
- Benson AB, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed February 15, 2018.
- Benson AB, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology. Rectal Cancer, version 1.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed March 12, 2018.
- Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773–779.
- Andre T, Lonardi S, Wong S, et al. Nivolumab + ipilimumab in patients with DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer: first report of the full cohort from CheckMate-142 [abstract]. Presented at the 2018 Gastrointestinal Cancers Symposium, January 18–20, 2018, San Francisco, California. Abstract 553.
- Overman MJ, Bergamo F, McDermott RS, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer: long-term survival according to prior lines of treatment from CheckMate-142 [abstract]. Presented at the 2018 Gastrointestinal Cancers Symposium, January 18–20, 2018, San Francisco, California. Abstract 554.
- Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138:2073–2087.
- Gatalica Z, Vranic S, Xiu J, et al. High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine. Fam Cancer 2016;15:405–412.
- Bristol-Myers Squibb Company. Nivolumab (Opdivo) prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s034lbl.pdf. Accessed February 15, 2018.
- Mecklin JP, Järvinen HJ. Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 1991;68:1109–1112.
- Merck Sharp & Dohme Corp. Pembrolizumab (Keytruda) prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s019s023lbl.pdf. Accessed February 16, 2018.
- Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Semin Oncol 2011;38:511–520.
- gov. Combination chemotherapy with or without atezolizumab in treating patients with stage III colon cancer and deficient DNA mismatch repair. Available at: https://clinicaltrials.gov/ct2/show/NCT02912559. Accessed February 24, 2018.
- The ASCO Post Evening News. Nivolumab shows promise in refractory, metastatic anal cancer. June 14, 2016. Available at: http://www.ascopost.com/News/41663. Accessed February 16, 2018.
- Ott PA, Piha-Paul A, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 2017;28:1036–1041.
- Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018 Feb 14 :JCO2017776385.
- Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities, version 1.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed March 12, 2018.
- Mustian KM, Sprod LK, Janelsins M, et al. Exercise recommendation for cancer-related fatigue, cognitive impairment, sleep problems, depression, pain, anxiety, and physical dysfunction: a review. Oncol Hematol Rev 2012;81–88.