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Managing mCRC

CE / CME

Opportunities and Challenges in Management of Metastatic Colorectal Cancer

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: May 02, 2023

Expiration: May 01, 2024

CME/CE Information

Activity

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Immune Checkpoint Inhibitors in MSI-High/dMMR mCRC

Patients with MSI-high/dMMR represent approximately 5% of patients who present with mCRC and may derive benefit from the ICIs pembrolizumab or nivolumab with or without ipilimumab.4,5,12

For patients with MSI-high/dMMR, first-line ICI therapy with pembrolizumab is the preferred option (based on KEYNOTE-177); another option is combined nivolumab and ipilimumab (an anti–CTLA-4 ICI). Pembrolizumab and nivolumab generally are better tolerated than chemotherapy and are recommended for patients regardless of their fitness for intensive therapy.4,5,12

The phase III KEYNOTE-177 study randomly assigned patients with MSI-high/dMMR mCRC and no previous treatment in the metastatic setting to receive pembrolizumab (n = 153) or standard-of-care chemotherapy with or without bevacizumab or cetuximab (n = 154), with coprimary endpoints of PFS and OS. Figure 1 shows the final analysis of these outcomes at median follow-up of 44.5 months, which demonstrated substantial benefit associated with pembrolizumab vs chemotherapy. Pembrolizumab was associated with a 41% reduction in risk of progression or death, while the trend toward improved overall survival was not statistically significant. Outcomes favored pembrolizumab across most prespecified subgroups, including BRAF mutation status. The objective response rate (ORR) was 45%, including 13% complete responses (CR) with pembrolizumab; in the chemotherapy arm, the ORR was 33%, including 4% with CR.16 In addition, patients who received pembrolizumab had fewer grade 3/4 adverse events and reported clinically meaningful improvements in health-related quality of life.17 

Figure 1. KEYNOTE 177: final analysis of first-line pembrolizumab vs chemotherapy in MSI-high/dMMR mCRC.16,17  

 

Expert Insights From Dr.Lentz: Survival outcomes with first-line pembrolizumab in MSI-high/dMMR mCRC

 

 

CheckMate 142 was a phase II study primarily designed to evaluate nivolumab plus ipilimumab for treatment of mCRC in previously treated patients, with 48-month PFS of 53% and OS of 71%.18 However, it also included 45 patients who received the combination as first-line treatment for metastatic disease. At a median follow-up of 29 months of these patients, ORR (primary outcome) was 69% and included 13% CR. The PFS and OS rates at 24 months were 74% and 79%, respectively.19 


Expert Insights From Dr.Lentz: Immune checkpoint inhibitors in BRAF-mutated mCRC

 

 

Based on KEYNOTE-177 and other data, pembrolizumab currently is indicated as treatment of unresectable or metastatic MSI-high/dMMR CRC, including as initial therapy and for subsequent therapy in ICI-naive patients.20 Nivolumab with or without ipilimumab currently is indicated as subsequent therapy for ICI-naive patients with MSI-high/dMMR who have progressed after initial chemotherapy.21 In addition, the NCCN guidelines recommend nivolumab with or without ipilimumab as a first-line treatment option for patients with unresectable or metastatic MSI-high/dMMR CRC.4,5 A third anti–PD-1 ICI, dostarlimab, has received accelerated approval for subsequent-line treatment of MSI-high/dMMR mCRC who have progressed on or after previous therapy and have no other satisfactory options.22 Selection of single agent or double immune checkpoint inhibitor therapy is best made by discussing risks and benefits of each option with the patient.

Which of the following best describes when ICI-related immune-related adverse events (irAEs) can occur?

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