Evaluating Immunotherapy in Nonmetastatic Colorectal Cancer

Oncology (Williston Park). 33(5):178-80.

Frank A. Sinicrope, MD

In this installment of Ask the PI, ONCOLOGY spoke with the lead investigator of the ATOMIC trial (ClinicalTrials.gov identifier: NCT02912559), Frank A. Sinicrope, MD, about utilizing immunotherapy in the adjuvant setting for colon cancer based on its impressive results in a subset of metastatic colorectal cancers.

Q:First, what immunotherapy agents are currently used in patients with colorectal cancer?

DR. SINICROPE: Currently, the use of immunotherapy in the treatment of colorectal cancer is restricted to a subset of metastatic tumors (~5%) that show deficiency in DNA mismatch repair.[1-3] These tumors have a defect in the ability to repair nucleotide mismatches in DNA, which results in microsatellite instability (MSI). MSI tumors are genetically unstable and carry numerous mutations that trigger the expression of neoantigens, which serve to attract abundant lymphocytes into the tumor. These “inflamed” tumors have been shown to respond favorably and, in some cases, dramatically to immune checkpoint inhibitors. The US Food and Drug Administration (FDA) has approved the use of immune checkpoint inhibitors for only those with metastatic colorectal cancers with MSI. Currently approved treatments include the anti–programmed death 1 (PD-1) antibodies pembrolizumab and nivolumab given as monotherapy, as well as the combination of nivolumab plus low-dose ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody.[1-3] Importantly, pembrolizumab was approved for the treatment of patients with any type of solid tumor with MSI, so it's not restricted to colorectal cancer. The combination of nivolumab and ipilimumab was shown to produce a higher response rate and better outcomes[3] when indirectly compared with nivolumab monotherapy from another study, and was associated with increased but manageable toxicities. Despite impressive results with these immunotherapy agents, it is important to note that only half of patients with metastatic disease demonstrate durable responses; therefore, studies to identify and circumvent resistant mechanisms are ongoing.

There are completed and multiple ongoing clinical trials to determine if the much larger group of non-MSI, or microsatellite stable, metastatic colorectal cancers might also benefit from immunotherapy, but thus far most of these studies have been negative. However, various strategies are being tested to see if we can increase the extent of inflammation within the tumor to better sensitize them to immunotherapy drugs.

Q:Can you tell us about the design of this new phase III trial that you are leading, including which patients are eligible?

DR. SINICROPE: The ATOMIC trial is looking to see if immunotherapy that has been effective in metastatic colon cancers with MSI due to DNA mismatch repair deficiency can be applied to earlier-stage disease, specifically nonmetastatic stage III colon cancer. Currently, the standard of care after surgical resection for stage III colon cancers is chemotherapy for 3 or 6 months, depending on risk grouping determined by T and N stage data. Adjuvant therapy, including immunotherapy for patients following surgical removal of their tumor, is directed towards eradicating micrometastases. This strategy using immunotherapy has been successful in patients with stage III melanoma, in which an immune checkpoint inhibitor was effective in reducing recurrence and death. So, we are using a similar tactic but selecting for patients with hypermutated colon cancer and applying this strategy to earlier-stage, nonmetastatic disease.

The ATOMIC trial is evaluating the standard chemotherapy regimen FOLFOX, which is a combination of fluorouracil, leucovorin, and oxaliplatin, and randomizing patients to either this regimen alone for 6 months or to this regimen combined with the anti–programmed death ligand 1 (PD-L1) immune checkpoint antibody atezolizumab. Atezolizumab is given together with this chemotherapy for 6 months and then is continued as monotherapy for an additional 6 months. We are looking to see if atezolizumab will improve the survival of these patients. Again, the study is targeted towards the group of patients whose tumors have MSI due to mismatch repair deficiency.

It's important to point out that it is now standard practice to test all newly diagnosed colon cancer patients for defects in mismatch repair. This is done in pathology laboratories around the country where, typically, the tumor is tested for the expression of four proteins (MLH1, MSH2, MSH6, and PMS2) that govern the DNA mismatch repair system in the cell. A patient's tumor tissue is stained for these proteins and if there is loss of one or more of these proteins, then this provides evidence for an inactivated or mutated gene, which can be a germline or heritable event (Lynch syndrome), or alternatively, inactivation of the MLH1 gene due to methylation, which is a sporadic event. Approximately 12% of stage III colon cancers show deficient mismatch repair-or MSI. The ATOMIC trial aims to accrue 700 patients total; we currently have 167 patients enrolled on the trial, so we are actively recruiting patients. An interim analysis for efficacy or futility is planned for when 50% of the projected outcome events have occurred.

Q: You mentioned the rationale for taking this immunotherapy strategy into the adjuvant setting. Is there preclinical or early clinical evidence for combining chemotherapy with immunotherapy in colorectal cancer?

DR. SINICROPE: An important yet incompletely understood issue is whether immunotherapy drugs should be given alone or combined with chemotherapy and, if so, in what sequence to achieve the best efficacy. Such an approach will likely need to be tumor type–specific; in colorectal cancer, there are limited data on the combination of chemotherapy plus immunotherapy. At this time, we have seen impressive efficacy for immune checkpoint inhibitors in the subgroup of metastatic colorectal cancers with MSI, but we do not know if the combination of chemotherapy plus immunotherapy is more effective than just giving immunotherapy alone. This issue is being addressed in an ongoing study being conducted by the NRG Cooperative Group in the metastatic setting (ClinicalTrials.gov identifier: NCT02997228). For the ATOMIC trial, patients are being treated with the intent to cure their disease, and adjuvant chemotherapy is of proven benefit and is standard of care. Accordingly, the initial way to study the potential benefit of immunotherapy is to look at its combination with standard chemotherapy and compare that with standard chemotherapy alone. In this way, we do not deprive patients of the chemotherapy that we know is effective in this setting.

Q:Are there other similar trials that are also testing novel adjuvant approaches for colorectal cancer that you could highlight?

DR. SINICROPE: The ATOMIC study is the only adjuvant trial in the United States that is currently looking at immunotherapy for the treatment of stage III colon cancer. There are ongoing discussions about evaluating molecularly targeted agents as adjuvant therapy for colon cancer, particularly for tumors with BRAF V600E mutations that are associated with worse prognosis in these patients. The ATOMIC study has the potential to be practice-changing in that it will determine whether immunotherapy is an effective treatment for the subset of colon cancers with MSI, where it has the best chance of being effective.

It is important to emphasize that immunotherapy has not been shown to benefit the majority of patients with colorectal cancer who do not have hypermutated tumors. Colorectal cancer is lagging behind some of the other tumor types in which immunotherapy has shown efficacy for a larger proportion of ptients. This is a very active area of research, to understand the factors that determine both the likelihood of response and the mechanisms underlying treatment resistance, such that we can overcome them so that more patients can receive and benefit from this remarkable new treatment.

Financial Disclosure: Dr. Sinicrope is a consultant to Roche/Ventana Medical Systems, which has products for mismatch repair testing.

PERSPECTIVE

Immunotherapy Promising for Metastatic MSI-H/dMMR Colorectal Cancer

Ronit Yarden, PhD, MHSA

Harnessing the immune system of a patient to fight his or her own cancer has been studied for many years. A breakthrough in immunotherapy that revolutionized the oncology field was achieved only after the discovery of a means to modulate immune checkpoints: via a pathway that enables tumor cells to display a cell-surface profile that resembles that of their normal counterparts, despite their differences, therefore evading antitumor immunity.

In 2017, the US Food and Drug Administration approved pembrolizumab, a checkpoint inhibitor that targets the programmed death 1 pathway, as a second-line treatment for all metastatic solid tumor types classified as microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR), including this type of colorectal cancer.

In the United States, colorectal cancer is the third most common diagnosed cancer type, and the second deadliest, in both men and women. However, only a small subset of colorectal cancer patients with metastatic disease have tumors with MSI-H or dMMR characteristics and are candidates for immunotherapy. Only those patients with Lynch syndrome, and those who randomly acquire alterations in one of the MMR genes, are eligible for immunotherapy.

In this interview, Dr. Sinicrope nicely summarizes the background, successes, and challenges of immunotherapy for the treatment of colorectal cancer. As the lead investigator of the phase III ATOMIC trial (ClinicalTrials.gov identifier: NCT02912559), he explains how this research builds on very positive survival data seen with immunotherapy in metastatic MSI-H/dMMR colorectal cancer, and aims to expand the utilization of immunotherapy for additional colorectal cancer patients.

While the trial is still restricted to MSI-H/dMMR colorectal cancer patients, it is set to determine whether patients diagnosed with stage III colorectal cancer would benefit from the combination of atezolizumab with the current standard of care, defined as surgery and an adjuvant chemotherapy regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX).

The ATOMIC trial is the only ongoing immunotherapy trial in stage III colorectal cancer patients. If successful, recurrence and death in stage III colorectal cancer patients with MSI would be reduced. Therefore, testing all patients for MSI is of interest, not only to increase patients' eligibility for the trial, but also to raise awareness about Lynch syndrome and family medical history of this condition. A positive trial outcome may ultimately open the door for additional studies, such as those focusing on whether the efficacy of immune checkpoint inhibitors could be extended as a single agent for MSI-H/dMMR tumors.

Finally, multiple ongoing studies are investigating the expansion of immunotherapy beyond immune checkpoint inhibitors in MSI-H/dMMR tumors to the broader population of colorectal cancer patients.

Financial Disclosure:Dr. Yarden has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Dr. Yarden is Director of Medical Affairs for the not-for-profit Colorectal Cancer Alliance, and former Assistant Professor and Researcher at Georgetown University, both in Washington, DC.

References:

1. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-13.

2. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182-91.

3. 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;36:773-9.