Back Back
Pembrolizumab in CRC
Immune Checkpoint Inhibitors: A Game Changer in GI Malignancies

Released: June 21, 2017

Expiration: June 20, 2018

Activity Information

Activity

Progress
1
Course Completed
Continue

For the first time, we have FDA approval for an immunotherapeutic agent in gastrointestinal cancers, as well as a groundbreaking first biomarker-driven approval of an agent across all solid tumors. On May 23, 2017, the anti–PD-1 antibody pembrolizumab received accelerated approval for microsatellite instability-high (MSI-H) or mismatch repair (MMR)–deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In addition, the agent was simultaneously approved for ALL unresectable or metastatic MSI-H or MMR-deficient solid tumors (pediatric and adult) that have progressed on previous treatment and with no satisfactory alternative treatment options.

This landmark approval is centered around the concept of microsatellite instability. Of interest, the understanding and knowledge about MSI has been around for decades. It was first used in the earlier stages of colon cancer to determine a couple of things: first, as a positive prognostic biomarker for early-stage CRC and, second, as a negative predictive factor to identify patients with stage II disease who are unlikely to benefit from adjuvant 5-FU.

DNA mismatch repair proteins (eg, MLH1, PMS2, MSH2) aid in the repair of DNA damage and errors that arise during replication. MMR gene germline mutations typically result in the setting of Lynch syndrome, with a second hit resulting in MSI-H tumors. In sporadic CRC, alterations that lead to DNA methylation (MLH1 gene) will lead to MSI-H.

Since 18% to 20% of patients with early-stage CRC will have MSI, universal screening has facilitated identifying patients at risk for Lynch syndrome, or hereditary nonpolyposis CRC. This allows tailored observation for affected patients and an opportunity to screen family members. 

In more advanced/metastatic CRC, MSI-H phenotype is only present in approximately 4% of the patients with most likely sporadic (nongermline) events. In contrast to earlier stages, MSI-H in stage IV CRC is associated with worse prognosis, likely owing to the fact that these tumors do not respond well to chemotherapy.

MSI-H tumors are associated with increased immune infiltration and expression of immune checkpoint regulators, which is why PD-1 checkpoint inhibitors such as pembrolizumab and nivolumab may have an important role in this disease. In addition, MSI-H tumors are associated with increased tumor mutation burden, with up to thousands of mutations per tumor. Hypermutated tumors produce tumor-specific neoantigens, which when expressed on the tumor cell surface become a prime target for T-cells. Taken together, these features will greatly improve the likelihood of response to immunotherapy and more specifically to checkpoint inhibitors such as pembrolizumab and nivolumab.

The Latest Data
The phase II study (Keynote-016) investigating pembrolizumab in MSI-H tumors included both MMR-proficient (microsatellite stable MSS) and MMR-deficient (MSI-H) CRC and multiple other MMR-deficient solid tumors. Focusing just on the CRC cohort, patients with MMR-deficient CRC had remarkable responses. The immune-related objective response rates were 40% for MMR-deficient CRC and 0% for MMR-proficient CRC. Most of the responders achieved durable responses. These findings established the first proof of concept that a checkpoint inhibitor such as pembrolizumab has profound activity in patients with MMR-deficient CRC.

Of interest, there were many significant responses in the MSI-H non-CRC cohort, with some patients achieving durable CRs.

Nivolumab demonstrated similar trends in a phase II study (CheckMate 142), thus confirming the role of targeting PD-1 in MMR-deficient CRC. In a recent update of the study results, heavily pretreated patients with MSI-H/MMR-deficient metastatic CRC, the ORR was 31% by investigator assessment with a 12-month OS of 74% (median not yet reached). This study also evaluated nivolumab in combination with the anti–CTLA-4 antibody ipilimumab, reporting a 41% ORR and 78% disease control rate with the combination at the expense of added toxicity. The role of dual inhibition remains unclear at this time.

Durable CR in a Patient With Refractory Metastatic Pancreatic Cancer in the Setting of Lynch Syndrome
A female patient in her mid-40s presented to my clinic with metastatic pancreatic cancer. The patient had already been diagnosed with colon cancer in her 20s, uterine cancer, and then presented with a new diagnosis of pancreatic cancer. She had initially received gemcitabine and nab-paclitaxel with no response before she was referred to my clinic. Since she had established Lynch syndrome, we sent the tumor for MSI testing, and it returned with the finding of MSI-H (germline MMR-deficient). With this finding, we enrolled her on the pembrolizumab trial discussed above. Within 2 months, the patient’s CA 19-9 level normalized and she appeared to have a good response on follow-up imaging. Following a few months of receiving pembrolizumab, her disease was in CR. At that point, the patient started to develop a rare form of immune-related neuropathy mostly manifested in the lower extremities. At that point, we discontinued her pembrolizumab, and the patient remains in CR more than 2 years out.

Rapid CR in a Patient With Sporadic MSI-H Metastatic CRC and Poor Performance Status
A 60-year-old female patient originally presented with what appeared to be an early-stage sigmoid cancer. She had presented with symptoms of obstruction and was treated with robotic resection at an outside facility. Her disease was determined to be at least stage IIIC. The patient was started on FOLFOX but did not tolerate it, with significant toxicities. In the meantime, she started to develop ascites with follow-up scans revealing significant progressive disease in the peritoneum. The patient was admitted to the hospital multiple times for obstruction and underwent multiple paracenteses. She was losing weight with a performance status of 2+. Discussions with the palliative care team included consideration of hospice. In the meantime, we were awaiting the results of her MSI testing. Her results suggested MSI-H, likely somatic with a high tumor mutational burden. The patient was started on pembrolizumab via compassionate use. Within 3 weeks, her CEA plummeted to undetectable levels, and her performance status improved dramatically to 0. Her ascites was near completely resolved. This was one of the most dramatic responses I have ever seen with pembrolizumab in this setting. Within 9 weeks, her disease was in near CR, and following 4 months of treatment, she was in CR and a normal CEA. She is back to her baseline and is planning a trip to Hawaii with her husband.

Key Takeaways 
Now, it is important to keep in mind that not all patients with MSI-high tumors will have a response. In fact, approximately 60% of these patients may have either a suboptimal response or even progressive disease. For this group of patients, ongoing studies continue to investigate mechanisms that drive resistance to PD-1 inhibitors. In addition, there is research exploring the role of immunotherapies in the other 96% of tumors that are MSS or MSI-L. Strategies include combining agents that will increase the level of infiltration of T-cells with inhibitors of PD-1. These agents include MEK inhibitors, Stat/Wnt inhibitors, BRAF inhibitors, multitargeted TKIs, and others. The first such proof-of-concept study with the MEK inhibitor cobimetinib and the PD-L1 inhibitor atezolizumab completed accrual with results pending.

Given the strength of the level of evidence, MSI should be universally tested across all stages of CRC. A recent paper published in Science suggested that MMR deficiency predicts response of solid tumors to PD-1 blockade. As such, I think that every attempt needs to be made to check for MSI/MMR deficiency in every patient with advanced-stage solid tumors as well. In the near future, I suspect that as, next-generation sequencing becomes part of routine clinical practice, validation of tumor mutational burden will facilitate identification of patients who are most likely to benefit from checkpoint inhibitors.

Your Thoughts?
How has your practice changed with the new approved indication for pembrolizumab? Are you more likely to test solid tumor patients for MSI/MMR? Please leave your feedback below.

Continue

Poll

1.
Has your practice of ordering MSI/MMR testing in patients with cancer changed since the approval of pembrolizumab for MSI-H metastatic CRC and all solid tumors?
Submit