Single-agent PD-1 blockade as curative-intent treatment in mismatch repair-deficient locally advanced rectal cancer
The single-arm Phase II study of dostarlimab will ultimately enroll 30 patients with clinical stage II and III dMMR rectal cancer. Of the 18 patients enrolled to date, 78% have T3 or T4 rectal tumors. All patients had dMMR and BRAF V600E wild-type tumors; the mean tumor mutational burden was 67.
Patients enrolled in the trial received the PD-1 monoclonal antibody dostarlimab at 500 mg intravenously every 3 weeks for 6 months, equaling 9 total cycles. The median follow-up for the analysis was 6.8 months, but four patients have been followed for nearly 2 years, and only four have received less than 6 months of the required treatment.
The majority of the patients achieved a clinical complete response (cCR) at 6 months, but some achieved it at 3 months as well. In terms of safety, no grade 3 or 4 adverse events were observed. In dMMR rectal cancer, PD-1 blockade may be able to either replace chemotherapy, replace chemotherapy and radiation therapy, or replace chemotherapy, radiation, and surgery. The study results suggest that the third possibility could become a reality.
“Neoadjuvant dostarlimab for 6 months represents a promising new treatment for patients with stage II/III dMMR rectal cancer [and] larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival endpoints are needed. It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.” – Expert Opinion.
CONCLUSION
GSK received the accelerated Jemperli FDA approval to treat adult patients with mismatch repair deficient (dMMR) recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options. Approximately 5% to 10% of rectal cancers are dMMR, which confers resistance to chemotherapy.
The drug has shown unprecedented results, and we should focus on the fact that the majority of the patients had big bulky tumors, and 94% were node-positive. Moreover, after the treatment, no patient required chemotherapy, radiation, or surgery after the treatment, and no disease recurrences have been observed to date.
Pharmaceutical companies having their products in the late stage of clinical development of Metastatic Colorectal Cancer include Hutchison Medipharma (fruquintinib), Isofol Medical (arfolitixorin) , Sumitomo Dainippon Pharma (napabucasin/BBI-608), G1 Therapeutics (trilaciclib + Chemotherapy) , Merck (Olaparib ± Bevacizumab) and AB Science (masitinib + Chemotherapy).
