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ICI已被证明对多个类型的实体瘤有效，包括具有较高微卫星不稳定性（high microsatellite instability，MSI-H）或DNA错配修复缺陷（dMMR）的肿瘤。截至目前，美国食品和药物管理局（Food and Drug Administration，FDA）已批准四种ICI用于治疗晚期MSI-H/dMMR型结直肠癌。
如果患者的结直肠肿瘤在ICI治疗期间缩小或保持稳定，那么医生可能会在两年后停止其免疫疗法。此外，部分患者也可能因为无法控制的副作用而提前停止ICI治疗。该研究资深作者、德克萨斯大学MD安德森癌症中心（MD Anderson Cancer Center）胃肠道肿瘤内科副教授
Van Morris
博士（MD）表示，停止有效的治疗方案无疑会让患者陷入紧张，担心治疗效果也会随之消失。
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Patients With Metastatic Colorectal Cancer May Continue Benefitting From Immunotherapy After Treatment Discontinuation
The majority of patients with metastatic colorectal cancer whose cancer did not progress during initial treatment with immune checkpoint inhibitors (ICIs) had no disease progression two years after discontinuing treatment, according to results published inCancer Research Communications , a journal of the American Association for Cancer Research (AACR).
ICIs have proven effective against certain solid tumors, including those with a high microsatellite instability (MSI-H) or deficient DNA mismatch repair (dMMR) status. To date, four ICIs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced MSI-H/dMMR colorectal cancer.
When patients’ colorectal tumors shrink or remain stable during ICI treatment, physicians may discontinue their immunotherapy after two years. Some patients may also cease ICI therapy earlier due to unmanageable side effects. Stopping a treatment regimen that was working can make patients nervous that the benefits will stop as well, explained Van Morris, MD , senior author of the study and an associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center.
“Patients very understandably get afraid at the prospect of stopping a therapy which appears to be working and often does not cause many side effects. They’ve had a diagnosis of stage 4 colorectal cancer, and they wonder about the chance of their cancer coming back if they stop treatment,” Morris said. “When we set out to do this study, we didn’t know the odds.”
Morris and colleagues—including the study’s first author Kristen Simmons, MD , a hematology/oncology fellow at Baylor College of Medicine—performed a retrospective analysis of 64 patients with MSI-H/dMMR metastatic colorectal cancer who were treated with an ICI targeting PD-1 or PD-L1, alone (48 patients) or in combination with an ICI targeting CTLA-4 (16 patients). All patients had experienced a durable benefit at the time of treatment cessation; 48 patients discontinued treatment due to a prolonged benefit, and 16 discontinued treatment due to side effects. Patients had received ICI therapy for a median of 17.6 months.
At a median of 22.6 months after stopping immunotherapy, 88% of patients had not experienced a recurrence. The progression-free survival rate after cessation of immunotherapy was 98% at one year, 91% at two years, and 84% at three years post-treatment. The rates were not significantly different whether patients had discontinued treatment due to side effects or due to a prolonged response.
The researchers investigated other factors that may influence the likelihood of relapse after treatment cessation. No significant differences in progression rates were observed whether patients had received single-agent or combination ICI therapy; whether or not they had metastases to the liver, peritoneum, or lymph nodes; and whether or not their tumors had mutations in KRAS, NRAS, or BRAF. Patients with lung metastases had a higher chance of recurrence than patients without lung metastases, a finding Morris said requires further investigation.
Morris suggested that these data may alleviate the fears of physicians who may not want to discontinue a patient’s treatment because of high-risk tumor characteristics. “We often hear from oncologists that they don’t feel comfortable stopping treatment on a patient with a BRAF mutation, for instance. But we did not see any association between mutation status and the likelihood for the cancer to recur,” Morris said.
Seven of the eight patients whose tumors progressed after stopping treatment were placed back on ICI therapy. Of note, all seven patients experienced a response or stable disease following rechallenge with ICIs.
“These data provide important information that oncologists can use for guiding discussions with patients with MSI-H/dMMR colorectal cancer by providing clearer numbers for the likelihood of progression should they decide to stop their immunotherapy treatment,” Morris said. “If you tell patients that, based on these data, there’s an 88% chance that their cancer won’t come back if they come off of therapy, I think they may be more accepting of that decision to stop treatment.”
Limitations of this study include its retrospective nature, as well as the relatively small sample size, which limits the statistical power of subgroup analyses. Further, the cohort included patients from a single cancer center, which may limit the applicability of the data to patients in other locations.
This study was funded by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the Andrew Sabin Fellow Family Foundation, and the Col. Daniel Connelly Memorial Fund. Morris reports research funding received from Pfizer, Novartis, Bicara Therapeutics, Bristol Myers Squibb, and BioNTech, as well as consulting relationships with Regeneron Pharmaceuticals and Novartis.
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