Leonard B. Saltz, MD
Assessing Eligibility in a Small Patient Subset
Until recent studies were reported, immunotherapy was thought to be ineffective for colorectal cancer; this article provides guidance on how to incorporate immunotherapy into this setting.
This article provides guidance on how to incorporate immunotherapy into colorectal cancer care. We review the identification of appropriate patients, available immunotherapy agents, benefits and risks of therapy, and how to overcome potential barriers to access. With recent US Food and Drug Administration approvals of two programmed death 1 (PD-1) receptor inhibitors for use in colorectal cancer, and dual therapy with combined nivolumab (PD-1) and ipilimumab (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] blocking antibody), it is vital that oncology providers be aware of how and when to implement these therapy options.
Colorectal cancer is the third leading cause of cancer-related deaths in the United States and is expected to cause approximately 50,630 deaths during 2018. Chemotherapy with fluorouracil (5-FU)–based regimens has been the gold standard for treatment, but with the 5-year survival rate for metastatic disease at only 12%, additional treatment options are highly needed. Recent groundbreaking cancer research utilizes immunotherapy, which is now considered a key treatment for many other tumor types, such as melanoma and non–small-cell lung cancer. As a result, oncology care providers are now being tasked with integrating immunotherapy into their daily practice for patients, including those with colorectal cancer.
In general, colorectal cancer has been impervious to immunotherapy, except for a small subset of patients with hypermutated tumors due to a deficient DNA mismatch repair protein. These cancers are referred to as microsatellite instability high (MSI-H). They tend to have high mutational burden and increased tumor neoantigen load, which is coupled with a dense immune cell infiltration. About 15% of all colorectal cancers harbor this now targetable molecular underpinning. Approximately 2.5% of MSI-H colorectal cancers arise from a genetic inheritance associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), and 12.5% are sporadic. The majority of colorectal cancers (85%) have no microsatellite instability and are referred to as microsatellite stable (MSS). Dudley et al evaluated responses to programmed death 1 (PD-1) therapy with pembrolizumab and reported a 0% response rate for patients with mismatch repair–proficient colorectal cancers. In contrast, the objective response rate was 52% in patients with mismatch repair –deficient colorectal cancers.
Until these recent studies were reported, immunotherapy was thought to be ineffective for colorectal cancer. Now, intensive research is ongoing to improve outcomes for both MSI-H and MSS disease unresponsive to immunotherapy. In particular, various clinical trials are exploring strategies to alter the immune inhibitory tumor microenvironment.
In normal tissue, mismatch repair proteins correct errors in DNA during replication. Tumors with mismatch repair deficiency are missing one or more of these mismatch repair proteins, resulting in a large number of DNA errors, which creates a hypermutated tumor. These errors are often noted in microsatellites, which are a small part of the DNA strand that is repeated. The microsatellites can be longer or shorter than normal due to DNA errors, making the errors easier to identify. Once errors are identified, the tumor tissue is labelled MSI.
The National Comprehensive Cancer Network (NCCN) guidelines recommend MSI testing for all patients with metastatic colorectal cancer. Several testing methods are available, including immunohistochemistry, polymerase chain reaction, and next-generation sequencing. Deciding which test to order often depends on cost to the patient and institutional availability.
Immunohistochemistry is commonly used and can detect the majority of mismatch repair –deficient tumors. It evaluates four different markers (MLH1, MSH2, PMS2, and MSH6) to predict mismatch repair status. If all four proteins are intact, then the tumor is considered mismatch repair–proficient, or MSS. Loss of one or more of these markers signals that the patient has a mismatch repair– deficient or an MSI-H tumor. From 5% to 11% of MSI-H tumors will not show protein loss but will show a retained antigen of a nonfunctional protein. Immunohistochemistry is widely considered the most cost-effective method.
Polymerase chain reaction analysis looks at five different microsatellites. It involves amplification of the microsatellites in tumor and normal tissues and comparison of the shifts between them. New shifts in the tumor sample not found in the corresponding normal sample indicate the presence of MSI. A shift in the size of at least 2 of the 5 regions is needed to be considered MSI-H.[3,4] Normal tissue is not always available, which can make this test problematic.
Next-generation sequencing is now available to most patients via commercial or academic entities. Its broad genomic sequencing looks for the MSI and also for hundreds of other mutations, which may open future doors for treatment. Unfortunately, it is expensive, and not all insurance companies cover it, which is a deterrent for many. When a company is chosen to perform the testing, we encourage patients to review its financial assistance programs. The amount of assistance provided is often based on household income and actual insurance coverage.
As testing becomes more prevalent, which MSI-H patients with colorectal cancer should be referred for genetic counseling needs to be considered. At the very least, young patients or patients with a strong family history of cancer and an MSI-H cancer may need genetic testing, as these are concerning for a primary germline mutation and Lynch syndrome. This is especially true of tumors not associated with BRAF mutations, since BRAF mutations are more commonly seen in sporadic cancers. Lynch syndrome is an autosomal dominant genetic disorder that carries a significant risk of colon cancer, as well as endometrial, ovarian, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin cancers. Carrying this genetic mutation has a significant impact not only on the patient’s treatment and prognosis but also on family members and cancer screening recommendations.
Because immunotherapy unbridles the body’s immune response, this can lead to dangerous adverse effects (AEs) with the potential for life-threatening toxicity. Patients with a prior history of autoimmune disorders have been excluded from immunotherapy trials due to the risk of “ramping up” the immune response in patients who already have an overactive immune system. Immunotherapy often exacerbates autoimmune conditions. In a cohort of 30 patients with prior autoimmune disease treated with ipilimumab, 27% experienced exacerbation of their condition, 33% had high-grade adverse reactions, and 1 death was reported related to colitis. Patients who have had transplants are also excluded for fear of transplant rejection with an immune system now on high alert for foreign tissues. Lipson et al reported a renal transplant rejection during pembrolizumab treatment. On the other hand, Hertz et al reported ipilimumab tolerability in three renal transplant patients.[7,9] Chronic steroid users also are excluded from immunotherapy trials because steroids are thought to dampen the treatment effect. Again, actual data on treating patients who have autoimmune disorders with immunotherapy are lacking, and caution should be used in this patient population. The choice is very personal and requires an in-depth conversation about the potential risks vs benefits with the patient. For example, a flare in an autoimmune condition such as psoriasis is typically manageable, but a multiple sclerosis flare could be life-threatening if exacerbated by immunotherapy.
Immunotherapy is generally well-tolerated and lacks the typical chemotherapy AEs such as nausea, vomiting, neuropathy, taste bud changes, and severe fatigue. However, at this time, no immunotherapy agents given alone or in combination are recommended by the NCCN guidelines for the majority of patients with colorectal cancer. For patients with MSS tumor types, no immunotherapy agent is currently approved by the US Food and Drug Administration (FDA). For these patients, access to new immunotherapy agents requires enrollment in a clinical trial. Only colorectal cancer patients with metastatic MSI-H tumors meet current treatment guidelines for immunotherapy.
Popat et al systematically reviewed previously collected data on systemic therapy for patients with stage II and III MSI-H colorectal cancer. They noted two prior studies that looked directly at the potential benefit of adjuvant 5-FU for these patients. MSS colorectal cancer patients had a significant survival benefit from adjuvant 5-FU, but there was no benefit in MSI-H colorectal cancer patients. Most clinical studies have supported this finding; however, in 2011, Sinicrope et al reported some benefit from 5-FU–based chemotherapy in patients with stage III MSI-H colorectal cancer who had suspected germline mutations; in particular, there were reductions in distant recurrences. At this time, no adjuvant therapy is recommended for stage II MSI-H colorectal cancer, as no clinical benefit has been shown and these patients have good outcomes (delayed time to recurrence and fewer distant metastases) compared with MSS tumors. For stage III MSI-H colorectal cancer, chemotherapy with 5-FU and oxaliplatin is typically advised due to the potential for some clinical benefit. There are various ongoing studies looking into the use of programmed death (PD)-1 inhibitors for potential adjuvant therapy, but they are not recommended at this time in this patient population.
Two PD-1–blocking antibody drugs are now indicated for use in patients with unresectable or metastatic MSI-H colorectal cancer. Nivolumab is approved for patients with MSI-H colorectal cancer after progression on systemic chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan. In the CheckMate 142 study, 74 patients received nivolumab at a dose of 3 mg/kg every 2 weeks. At 12 months, 23 (31%) patients achieved an objective response. The disease control rate was 69%. However, according to the NCCN guidelines, initial single-agent immunotherapy may be chosen for patients with unresectable, advanced metastatic disease who are not appropriate candidates for intensive therapy.
Pembrolizumab is approved for all solid tumors with mismatch repair deficiency regardless of histology after failure of first-line, standard-of-care treatment. Colorectal cancer patients are expected to have progression on treatment with fluoropyrimidine, oxaliplatin, and irinotecan. In a phase II study of pembrolizumab in patients with MSI-H solid tumors, 46 of 86 patients (53%) had an objective response and 18 patients (21%) achieved a complete radiographic response. Remarkably, in a heavily pretreated patient population, the median duration of response and overall survival was not reached after a median follow up of 12.5 months. The FDA approval was based on data from 5 clinical trials and a total of 149 patients. In the 90 patients with MSI-H colorectal cancer, the objective response rate was 36%.
Since the two PD-1 inhibitors are similar, ultimately it is the provider’s choice. Some oncologists prefer pembrolizumab over nivolumab because of its across-the-board approval for MSI-H solid tumors. Dosing is also a major consideration. The nivolumab package insert recommends 240 mg every 2 weeks for MSI-H colorectal cancer. Some extrapolate use of 480 mg every 4 weeks from its use in other indications. Pembrolizumab is given at 200 mg every 3 weeks.
Is there also potential for combination treatment with immunotherapies? Overman et al evaluated the benefit of dual therapy with combined nivolumab (a PD-1–blocking antibody) and ipilimumab (a CTLA-4–blocking antibody) in 119 patients with MSI-H colorectal cancer. The progression-free survival rate was 76% at 9 months and 71% at 12 months. The overall survival rate was 87% at 9 months and 85% at 12 months. The combination showed an objective response rate of 55% and a disease control rate for 12 weeks or more of 80%. However, there were higher rates of grade 3 and 4 toxicities. While promising, these data are not from a randomized study and therefore may not support the routine use of a more toxic, more expensive regimen when a good alternative exists. The FDA recently approved an indication of nivolumab/ipilimumab combination for patients with MSI-H metastatic colorectal cancer following progression on fluoropyrimidine, oxaliplatin, and irinotecan, and this regimen can now be considered for select patients.
Leonard B. Saltz, MD
Assessing Eligibility in a Small Patient Subset
Immunotherapy has revolutionized the care of a number of malignancies, including melanoma, renal cell carcinoma, and non–small-cell lung cancer, to name a few. For most patients with colorectal cancer, however, effective immunotherapy remains unavailable. In this article, Wilt and Le review the data supporting the use of programmed death 1 (PD-1) inhibitors-both alone and in combination with a low-dose cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor-in patients with metastatic microsatellite instability–high (MSI-H) colorectal cancer.
It is important that clinicians note the small percentage of the colorectal cancer population that actually has MSI-H disease. As noted by Wilt and Le, approximately 15% of new colorectal cancer cases are MSI-H. However, MSI-H is a favorable prognostic indicator in early-stage disease, and this means that a substantial proportion of individuals with stage I, II, or III MSI tumors will never develop metastatic cancer. As a result, only 3% to 4% of metastatic colorectal cancer patients have MSI tumors. For the other 96% of patients with metastatic disease, currently available immunotherapies are ineffective and should not be used. Numerous clinical trials of novel immunotherapeutic agents and strategies are currently in progress, and providers should strongly encourage patients with metastatic microsatellite-stable colorectal cancer to consider enrolling.Eligibility for immunotherapy can be assessed using immunohistochemistry (IHC) for mismatch repair status, polymerase chain reaction (PCR) for MSI status, or a multigene next-generation sequencing (NGS) assay. While IHC has the shortest turnaround time and is currently the most widely used approach, the ability of NGS assays to combine MSI data with mutational information, such as KRAS, NRAS, and BRAF status, will likely render this approach the preferred technique going forward.Dr. Saltz is a Medical Oncologist; Executive Director for Clinical Value & Sustainability; Head, Colorectal Oncology Section, Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, New York, New York
As the appeal of immunotherapy grows among patients, many desire to utilize it as a first-line treatment. The results of KEYNOTE-177, a phase III randomized study comparing first-line use of pembrolizumab with investigator-choice chemotherapy for mismatch repair–deficient or MSI-H metastatic colorectal cancer, will help providers evaluate if immunotherapy is an option for the first-line treatment of MSI-H metastatic colorectal cancer.
Immunotherapy can result in a wide range of toxicities and AEs that can occur at any point in therapy. Most are noted within weeks to the first 3 months of treatment; however, first onset of an AE has been documented as late as a year after discontinuing treatment. Providers must have a clear understanding of potential toxicity and a firm grasp on management. Immunotherapy can cause organ inflammation in any part of the body. Life-threatening side effects, while rare, can occur and require rapid identification and management (Table 1). Given the wide range of AEs and toxicities, providers should familiarize themselves with the National Cancer Institute’s Common Terminology Criteria for Adverse Events and its descriptive terminology, which can be utilized for grading AEs. The grading scale ranges from 1 (minimal) to 5 (death). Once an AE is graded, the NCCN recommendations for treatment of toxicity can be implemented. Broad guidelines for grading and treatment are noted in Table 2.
Follow-up and laboratory monitoring are key to identifying potential toxicities early. The majority of toxicities are low grade and respond well to symptom management. For example, low-grade pruritus can respond to antihistamines, rash to topical steroids, and arthralgias to nonsteroidal anti-inflammatory
drugs. Thyroid dysfunction, which is often identified by laboratory results before the patient reports symptoms, is easily treated with hormone replacement. However, the potential for high-grade toxicities such as pneumonitis and colitis requires prompt evaluation and, depending on severity, treatment with steroids. When given orally, prednisone 1 mg/kg or its equivalent is often recommended, with tapering to begin once symptoms improve. For more serious toxicities, hospitalization may be necessary for intravenous steroid treatment. If symptoms fail to improve in 2 to 3 days after starting steroids, then early (~72 hours) addition of immunosuppressive drugs, such as infliximab, may be considered, along with specialist consultation.[7,17] Infliximab has been noted to be particularly effective for immune-related colitis and inflammatory arthritis. If considering infliximab use, the patient needs to have testing for tuberculosis, hepatitis B, and hepatitis C, since the drug can cause their reactivation. However, in an acute setting, it is not recommended to await test results before starting infliximab. Infliximab should also not be given to patients with immune-related hepatitis, as it is known to be hepatotoxic.[7,17] Other considerations in treating immunotherapy-related toxicities are that tissue biopsy may be required to determine the exact etiology, and referral to a specialist is often warranted. It is also vital to educate patients to have open communication with providers, so that early signs of toxicity are not overlooked. The recently published NCCN guidelines for treating toxicity in this special patient population can be a useful clinical tool.
Duration of treatment is largely influenced by treatment response and tolerability. In the phase II study with pembrolizumab, patients were treated for a maximum of 2 years. The average time to response was 21 weeks and to complete response was 42 weeks. Eleven patients with complete responses were taken off therapy after 2 years and followed by surveillance. At last report, no evidence of cancer recurrence was observed, and their average time off therapy was 8.3 months. An additional 7 patients with residual disease on scans also discontinued therapy at 2 years or earlier because of toxicity. The average time off therapy at publication was 7.6 months, with no evidence of progression at the data cutoff. In the nivolumab phase II study, patients were treated indefinitely, and average time to response was 2.8 months. At publication, the median response duration had not yet been reached, all responders were alive, and 8 patients had responses lasting longer than 12 months. Similarly, the combination therapy of nivolumab and ipilimumab did not reach the median duration of response at the time of data collection cutoff. The durable responses seen during these studies are very encouraging, but the actual length of treatment needed to achieve them remains to be clarified.
With recent FDA approvals and the addition of these immunotherapies to the NCCN drug compendium, insurance approval should be less of an issue if MSI status has been documented. Both PD-1 manufacturers, Merck and Bristol-Myers Squibb, offer assistance programs; exact coverage depends on income. Since the online application takes 7 to 10 days to process, interested patients should apply as soon as they are being considered for therapy.
Immunotherapy offers exciting new treatment options with lasting results. It is vital that providers test patients for molecular alterations, such as MSI status. MSI testing should be routine for all patients with colorectal cancer and can be performed with immunohistochemistry, polymerase chain reaction, or next-generation sequencing. Two PD-1–blocking antibodies, nivolumab and pembrolizumab, are available for clinical use. The first combination immunotherapy treatment with nivolumab and ipilimumab was also recently approved for use in MSI-H colorectal cancer. For patients with MSI-H colorectal cancer, durable responses can be achieved with immunotherapy agents. While high-grade toxicity is a risk, it is usually manageable with steroids if diagnosed and treated early. As extensive research continues, providers are encouraged to stay up-to-date on treatment guidelines and recommendations in the ever-changing world of colorectal cancer treatment.
Financial Disclosure: Dr. Le serves on the advisory board and receives research funds from Bristol-Myers Squibb and Merck; she also receives speaker’s honoraria from Merck. Ms. Wilt has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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11. Merck. Keytruda (pembrolizumab) package insert. Available at: https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed September 9, 2018.
12. Bristol-Myers Squibb. Opdivo (nivolumab) package insert. Available at: http://www.opdivohcp.com. Accessed September 9, 2018.
13. Diaz LA, Le DT, Yoshino T, et al. KEYNOTE-177: First-line, open-label, randomized, phase III study of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma. J Clin Oncol. 2016;34(suppl 4).
14. Common terminology criteria for adverse events (CTCAE). Version 5 (November 27, 2017). Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed September 9, 2018.
15. Management of immunotherapy-related toxicities (February 14, 2018). Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed June 1, 2018.