Interim results of neoadjuvant immunotherapy with prolgolimab in patients with locally advanced MSI / dMMR colorectal cancer

   Introduction: Colorectal cancer is one of the leading malignancies in Russia [1]. The standard approach for selected patients (pts) with locally advanced colon cancer is surgery with adjuvant chemotherapy. Several studies have shown that colorectal cancer (CRC) with presence of a disorder in the mismatch repair (dMMR) / microsatellite instability (MSI) is characterized with high sensitivity to the immune checkpoint inhibitors. Several studies have shown that MSI / dMMR CRC patients tend to be more responsive to immune checkpoint inhibitors such as pembrolizumab, nivolumab or ipilimumab. However, there was no information about the efficacy of prolgolimab, a PD-1 receptor blocking antibody. Prolgolimab was highly effective in melanoma treatment, while the toxicity was comparable to pembrolizumab and nivolumab.

   Methods: We initiated the phase II non-randomized open-label clinical trial. Inclusion criteria were: histologically verified, MSI / dMMR, clinical stage II–III CRC. According to study protocol, prolgolimab (1 mg / kg) is administered every two weeks, then surgery should be done after 6 months of immunotherapy (12 cycles). In case of surgical treatment refusal, the systemic treatment proceeds for 1 year. The co-primary endpoint was the complete response (pCR) rate. Secondary endpoints included tumor regression grade by Mandard (TRG), major pathologic response (MPR), overall response rate (ORR) disease free survival (DFS) and overall survival (OS). Here is a presentation of safety and pathologic response data — rates of pCR / MPR, objective response rate.

   Results: A total of 26 patients began treatment with prolgolimab from April, 2022 to February, 2024. Immune-related adverse effects of grade III–IV, were recorded in 1 (3,8 %) patient (autoimmune hepatitis grade IV); 4 (15,4 %) patients had adverse effects grade I–II: autoimmune thyroiditis, diarrhea, hypothyroidism. Two patients were refused to make a surgical treatment because of clinical CR and possible volume of surgery. Nine (34,6 %) patients underwent surgical treatment within 3 months after the immunotherapy completion: 7 patients had TRG 1 and pCR, 2 — TRG 2 and MPR after the treatment. ORR was 100 %, complete clinical response rate 40 %. The study is still ongoing, DFS and OS will be announced in further publications. Median follow-up time was 5 months.

   Conclusion: The first interim analysis data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches in MMR / MSI CRC patients.

1. Malignant tumors in Russia in 2021 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shachzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022.252 p. (In Russ.)

2. Sung H., Ferlay J., Siegel R.L., et al. Global сancer ыtatistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209–249. doi: 10.3322/caac.21660

3. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69(1):7–34. doi: 10.3322/caac.21551

4. Jensen L.H., Kjaer M.L., Larsen F.O., et al. Phase III randomized clinical trial comparing the efficacy of neoadjuvant chemotherapy and standard treatment in patients with locally advanced colon cancer: The NeoCol trial. J Clinical Oncol 2023;41(17):LBA3503-LBA3503(2023). doi: 10.1200/JCO.2023.41.17_suppl.LBA3503

5. Fedyanin M.Yu., Gladkov O.A., Gordeev S.S., et al. Practical recommendations for drug treatment of cancer of the colon, rectosigmoid junction and rectum. Zlokachestvennie opuholi = Malignant Tumors 2023;13(3s2):425–482. (In Russ.). doi: 10.18027/2224-5057-2023-13-3s2-1-425-482

6. Zhang X., Wu T., Cai X., et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: new strategies and unveiled opportunities. Front Immunol 2022;13:795972. doi: 10.3389/fimmu.2022.795972

7. Tryakin A.A., Fedyanin M.Yu., Tsukanov A.S., et al. Microsatellite instability as a unique characteristic of tumors and a predictor of response to immune therapy. Zlokachestvennie opuholi = Malignant tumours. 2019;9(4):59–69. (In Russ.). doi: 10.18027/2224-5057-2019-9-4-59-69

8. Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 2012;13(11):1152–1160. doi: 10.1016/S1470-2045(12)70348-0

9. Cercek A., Fernandes G.D.S., Roxburgh C.S., et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res 2020;26(13):3271–3279. doi: 10.1158/1078-0432.CCR-19-3728

10. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 2019;38(1):255. doi: 10.1186/s13046-019-1259-z

11. Le D.T., Uram J.N., Wang H., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596

12. Maio M., Ascierto P.A., Manzyuk L., et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol 2022;33(9):929–938. doi: 10.1016/j.annonc.2022.05.519

13. Andre T., Amonkar M., Norquist J.M., et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22(5):665–677. doi: 10.1016/S1470-2045(21)00064-4

14. Lenz H.J., Van Cutsem E., Limon M.L., et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: The phase II CheckMate 142 study. J Clin Oncol 2022;40(2):161–170. doi: 10.1200/JCO.21.01015

15. Chalabi M., Fanchi L.F., Dijkstra K.K., et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26(4):566–576. doi: 10.1038/s41591-020-0805-8

16. Chalabi M., Verschoor Y.L., van den Berg J., et al. LBA7 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol 2022;33(7):S1389. doi: 10.1016/j.annonc.2022.08.016

17. Yuki S., Bando H., Tsukada Y., et al. Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol 2020;38(15):suppl. 4100. doi: 10.1200/JCO.2020.38.15_suppl.4100

18. Rahma O.E., Yothers G., Hong T.S., et al. Use of total neoadjuvant therapy for locally advanced rectal cancer: initial results from the pembrolizumab arm of a phase 2 randomized clinical trial [published correction appears in JAMA Oncol 2022 Jul 1;8(7):1073. JAMA Oncol 2021;7(8):1225–1230. doiorg/10.1001/jamaoncol.2021.1683

19. Ludford K., Ho W.J., Thomas J.V., et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol 2023;41(12):2181–2190. doi: 10.1200/JCO.22.01351

20. Cercek A., Lumish M., Sinopoli J., et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386(25):2363–2376. doi: 10.1056/NEJMoa2201445

21. Tjulandin S., Demidov L., Moiseyenko V., et al. Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice. Eur J Cancer 2021;149:222–232. doi: 10.1016/j.ejca.2021.02.030

22. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487(7407):330–337. doi: 10.1038/nature11252

23. Sun H., Nered S.N., Tryakin A.A., et al. Neoadjuvant chemoimmunotherapy for gastric cancer patients with microsatellite instability. Voprosy Onkologii 2023;69(2):275–284. (In Russ.). doi: 10.37469/0507-3758-2023-69-2-275-284

24. Tougeron D., Mouillet G., Trouilloud I., et al. Efficacy of adjuvant chemotherapy in colon cancer with microsatellite iInstability: a large multicenter AGEO study. J Natl Cancer Inst 2016;108(7). doi: 10.1093/jnci/djv438

25. Sargent D.J., Marsoni S., Monges G., et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer [published correction appears in J Clin Oncol. 2010 Oct 20;28(30):4664. J Clin Oncol 2010;28(20):3219–3226. doi: 10.1200/JCO.2009.27.1825

26. Chakrabarti S., Grewal U.S., Vora K.B., et al. Outcome of patients with early-stage mismatch repair deficient colorectal cancer receiving neoadjuvant immunotherapy : a systematic review. JCO Precis Oncol 2023;7:e2300182. doi: 10.1200/PO.23.00182

27. Gelsomino F., Barbolini M., Spallanzani A., et al. The evolving role of microsatellite instability in colorectal cancer : A review. Cancer Treat Rev 2016;51:19–26. doi: 10.1016/j.ctrv.2016.10.005

28. Pastorino A., Catalano F., Zalcberg J.R., Sobrero A. Cross-trial comparisons for the adjuvant treatment of MSI colorectal cancer: dare to dream the future scenarios. Eur J Cancer 2024;199:113538. doi: 10.1016/j.ejca.2024.113538

29. Sinicrope F.A., Mahoney M.R., Smyrk T.C., et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013;31(29):3664–3672. doi: 10.1200/JCO.2013.48.9591

30. Luchini C., Bibeau F., Ligtenberg M.J.L., et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden : a systematic review-based approach. Ann Oncol 2019;30(8):1232–1243. doi: 10.1093/annonc/mdz116.