Immune Checkpoint Inhibitors Improve Outcomes in Mismatch Repair Deficient CRC, but Can Induce irAEs

Treatment of colorectal cancer (CRC)—the third leading cause of cancer-related death in the United States—remains challenging even today. But according to leading oncologists in the field, who were speaking at a session at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, screening patients diagnosed with CRC for deficient mismatch repair (dMMR) could help create a roadmap for precision treatment.

Michael J. Overman, MD, The University of Texas MD Anderson Cancer Center, chaired the session and was the first presenter. During his presentation, Optimal Approach to Colorectal Cancer With Deficient Mismatch Repair, he said that microsatellite instability (MSI) and dMMR testing should be universal, especially in individuals who have a family history of CRC.

In terms of new treatment options, immune checkpoint inhibitors, namely the PD-1 inhibitors, nivolumab and pembrolizumab, now have added indications in the treatment of CRC:

• Nivolumab: MSI high (MSI-H) or dMMR metastatic CRC (mCRC) that has progressed on fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab: Adult and pediatric patients with unresectable or metastsic, MSI-H or dMMR that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

The National Comprehensive Cancer Network, Overman said, recommends nivolumab or pembrolizumab as a treatment option for patients with metastatic dMMR CRC as second- or third-line therapy.

The rationale here is based on studies showing that high tumor mutational burden can increase sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy.

Frameshift mutations in CRC can result in new neoantigen targets, including proteins involved in differentiation (melanocyte differentiation antigens), overexpressed proteins (HER2), viral proteins (HPV), etc. MSI-H tumors have a very high mutation rate, which, when combined with frameshift mutations, where a single alteration leads to multiple amino acids, results in mutations that have a qualitative and a quantitative mutation rate.

“In the clinic, we typically see patients present with a very high rate of mutation,” Overman said.

He noted however, that there remains significant discrepancy between the testing methodologies used to detect dMMR testing. MOSAIC testing, Overman said, is much more sensitive and more specific than PCR.

Overman’s group conducted studies comparing nivolumab and ipilimumab in patients diagnosed with dMMR/MSI-H CRC to investigate whether addition of the CTLA-4 inhibitor, ipilimumab, could further enhance outcomes compared with nivolumab alone, in this patient population who had received at least 2 prior lines of treatment. The study, which was published in the Journal of Clinical Oncology,¹ found investigator-assessed objective response rate (ORR) was 55% (95% CI, 45.2-63.8) and disease control rate for ≥12 weeks was 80%. At data cut off, the median duration of response was not reached and most responses were ongoing. Progression-free survival (PFS) rates were 76% (9 months) and 71% (12 months), and overall survival (OS) rates were 87% (9 months) and 85% (12 months).

Overman also drew attention to the results from KEYNOTE-164, which evaluated pembrolizumab in patients with MSI-H CRC who had received at least 2 prior lines of treatment. When data was acquired in October 2017, which was a median 12.6 months of follow up, ORR was 32% (95% CI, 21-45), with 2 complete responses and 18 partial responses. Median PFS was 4.1 months and 12-month PFS rate was 41%. The 12-month OS rate was 76%.²

“Questions remain, however, around the durability of nivolumab’s effect in dMMR CRC,” Overman said.

Several phase 3 trials are ongoing, he said, to test these immune checkpoint inhibitors in patients with MSI-H/dMMR CRC.

• NRG-G1004/SWOG-1610 is evaluating how well the combination of chemotherapy, bevacizumab, and/or atezolizumab will work in advanced MSI-H/dMMR CRC
• KEYNOTE-177 is evaluating the combination of pembrolizumab with mFOLFOX/bevacizumab in advanced MSI-H/CRC
• Alliance 021502 is evaluating combination chemotherapy and atezolizumab in stage II colon cancer and dMMR patients

“Pembrolizumab is now standard-of-care for dMMR non-CRC patients” Overman said, and he sees a way forward for success with these treatments, in combination with chemotherapy, in CRC as well.

Immune-Related Adverse Events

Another speaker during the session, Marc S. Ernstoff, MD, Roswell Park Comprehensive Cancer Center, gave an overview on the management of immune-related adverse events (irAEs) in mCRC.

Ernstoff posed the question, “Are oncologists comfortable with managing irAEs?” Sharing the results of a survey that was conducted, he showed that 32% of providers are very uncomfortable with managing irAEs, 5% are somewhat uncomfortable, 19% are somewhat comfortable, and 33% said they were very comfortable. showed that he said at least half of us are not comfortable.

A point to note, he said, is that immune toxicities in CRC may not necessarily be related to the specific antibody being administered. It’s important to understand that the effects are not immediate; rather one might be dealing with latent toxicity, and that these toxicities can affect any organ.

The most common among these toxicities are pruritis, rash, and diarrhea. These were more commonly observed when nivolumab was combined with ipilimumab, compared with when nivolumab was administered alone. The incidence of irAEs was relatively higher with ipilimumab alone.³

Syndrome recognition is vital, Ernstoff emphasized. Some of the more unusual symptoms include the development of diabetes, nephritis, myositis, myocarditis, and uveitis.

“A high percentage of low grade (<3) irAEs are common, even with single agents,” he said with 10%-25% of adverse events (AEs) remaining unresolved or lasting at least 12 months. He explained that a majority of patients may require steroid treatment for symptom resolution, especially if they are on combination immune checkpoint inhibitors.

Dealing with long-term irAEs is the biggest challenge of cancer survivorship in patients receiving these checkpoint inhibitors, he said.

It is vital to recognize the AEs; for low-grade AEs, symptom management can suffice, whereas for high-grade AEs, immunosuppression using glucocorticoids or infliximab/mycophenalate is recommended. Chronic immune suppression would require steroid treatment, anti-integrins, or anti—tumor necrosis factor agents.

Is mitigation an option? This remains an unknown for the time being, Ernstoff said. An individual’s genetic predisposition could be tapped into, along with boosting the microbiome, such as using probiotic agents. Another strategy could be identifying high-risk populations, including those with existing autoimmune disease or those who have had an organ transplant.

“Overall, immune checkpoint inhibition of the PD1/PD-L1 axis has been well tolerated and is safer than conventional chemotherapy,” Ernstoff said. He emphasized the importance of oncologists educating themselves and their immediate teams as well as their communities around the toxicity profile of these agents, especially because “irAEs can masquerade as other common symptoms.”

References

1. 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(8):773-779. doi: 10.1200/JCO.2017.76.9901.
2. Le DT, Kavan P, Kim TW, et al. KEYNOTE-164: Pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer. J Clin Oncol. 2018;36(suppl; abstr 3514).
3. Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21(10):1230-1240.