Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer Journal Club Summary

● MSI-H/dMMR Colorectal Cancer

○ CRC with presence of mismatch-repair deficiency (dMMR) → decrease response to traditional chemo and
high mutation burden
○ Colorectal cancer (CRC): most common cancer diagnosed in both men and women in the US
■ Lifetime risk for developing CRC ~4.3% and 4.0% for men and women, respectively
○ Risk factors for CRC: FH, sex (males), age, hx IBD, smoking, alcohol use, dietary factors, lack of
physical activity, obesity
● Guideline Recommendations for colorectal cancer (Cetuximab may be substituted for bevacizumab)
○ FOLFOX +/- Bevacizumab
■ Folinic acid
■ 5-fluorouracil
■ oxaliplatin
○ CAPEFOX +/- Bevacizumab
■ Capecitabine
■ Oxaliplatin
○ FOLFIRI +/- Bevacizumab
■ Folinic acid
■ 5-fluorouracil
■ Irinotecan
● Adding folinic acid (Leucovorin) to FOLFOX and FOLFIRI: Can enhance the binding of 5-FU to an enzyme
inside of the cancer cells, enhancing its effect.
● Pembrolizumab (Keytruda)
○ MOA:
■ Highly selective anti-PD1 monoclonal antibody that binds to/blocks PD1 receptor on T
cells
■ Inhibition of PD1 pathway between tumor cells and T-cells reverses T-cell suppression
and induces desired antitumor response
○ FDA Indication (Not currently approved for first line therapy)
■ Tx MSI-H-dMMR colorectal cancer in patients progressed following tx with
fluoropyrimidine, oxaliplatin, and irinotecan
○ Dosing:
■ 200mg IV Q 3 weeks or 400mg IV Q 6 weeks, depending on patient response
○ ADRs:
■ Fatigue, N/D, HA, decreased appetite, skin rash, pruritis, vitiligo, arthralgia, back pain,
hyperglycemia, hypertriglyceridemia, hyponatremia
Journal Club Article:
● Background: programmed death 1 (PD1) blockade has shown benefit in MSI-H or dMMR tumors AFTER
previous therapy, unclear about BEFORE
● Phase 3 randomized, multicenter, international, open-label
● 307 patients
● Tx options: pts randomly entered into these treatment groups
○ Pembrolizumab 200mg every 3 weeks
○ FOLFOX6
○ FOLFOX 6 + bevacizumab
○ FOLFOX + cetuximab
○ FOLFIRI
● Primary endpoints:
○ Progression free survival & overall survival
● Secondary endpoints:
○ Overall response & safety
● Inclusion:
○ >18 yrs old
 ○ Stage IV
○ ECOG stage 0-1
○ Adequate organ function
○ Prior chemo (completed >6 months prior to randomization)
○ dMMR
○ MSI-H
■ Local PCR analysis of 3-5 tumor analysis
● Study protocol:
○ Pts randomly assigned 1:1 ratio to Pembro or investigator’s choice of chemo
○ Regimens were repeated every 2 weeks (3 weeks for Pembro) up to max 35 treatments with
Pembro* (*or until disease progression, unacceptable tox, decision by physician, pt withdrawal)
○ Follow up: Every 9 weeks
● Statistical Analysis: Kaplan-meier (estimate PFS and duration of response), 2 interim analysis
● Baseline characteristics
○ Medium duration of treatment 11.1 months (Pembro) & 5.7 months (chemo group)
○ 57 pts completed all 35 treatments of Pembro
○ High percentage of pts who did not have prior systemic chemotherapy; point of this study is to look
at best first-line option for chemotherapy
● Endpoints:
○ Looked into if different patients responded better or worse; for most part, most patients responded
similarly
○ Primary endpoint:
■ PFS subgroup analysis: Overall majority of subgroups in pembro was superior to chemo
○ Secondary endpoint: Overall response and safety
■ Complete response:
● Pembro: 11.1% vs 3.9% in chemo
● Those that responded in Pembro group responded better than chemo group
■ Progressive disease:
● Pembro: 29.4% vs 12.3% in chemo
○ Duration of response:
■ Most patients had continued response with Pembro that there was no full data for it (need
to wait until final analysis) but in general, much higher than chemo
○ Safety Endpoints:
■ Grade 3 or higher events: 78% in chemotherapy, 56% in Pembro
■ D/C d/t ADE: Pembro 14%, chemo 12%
■ Infusion rxn: Pembro had higher incidence
● Limitations:
○ 59% either crossed over or recieved anti PD-1 therapy outside of the trial
○ No subgroup analysis of cross-over pts
● Conclusion
○ First-line pembro superior to standard of care
○ SIgnificance to Specialty Pharmacy:
■ Cost of therapy:
● every 3 weeks: $9,869.94
● Every 6 weeks: $19,739.88
■ Optum Specialty Pharmacy does not currently have access to pembrolizumab
■ Access is limited to select specialty pharmacies, infusion centers, cancer tx facilities
■ June 29, 2020 Pembrolizumab granted FDA-approval for first-line treatment of pts with
metastatic MSI-H dMMR CRC
● Clinical significance:
○ Follow up was 32.4 months; PFS was significantly longer with pembrolizumab vs chemotherapy
(16.5 vs 8.2 months)
○ Treatment related AEs significantly lower with pembrolizumab vs chemotherapy
○ Infusion reactions more common with pembrolizumab vs chemotherapy