The results of the use of immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab in the first line treatment of patients with metastatic gastric cancer. The experience of the oncological service of Moscow

Introduction: the use of immunotherapy agents in combination with chemotherapy has shown its effectiveness in randomized trials for the first-line treatment of metastatic gastric cancer. The paper considers the experience of the Moscow oncological service in evaluating the effectiveness of pembrolizumab and nivolumab in patients with metastatic gastric cancer, depending on morphological (CPS, MSI) characteristics.

Aim of the study: to compare progression-free survival (PFS) and overall survival (OS) in patients with advanced gastric cancer who underwent immunotherapy (as monotherapy or in combination with chemotherapy) or standard chemotherapy with oxaliplatin and fluoropyrimidines.

Patients and methods: 194 patients met the inclusion criteria. Of these, 52 patients received checkpoint inhibitors (ICI) (18-immunotherapy alone; 31-in combination with chemotherapy, 15 patients received pembrolizumab and 37 patients received nivolumab); 142 patients received chemotherapy CAPOX or FOLFOX without ICI. The median follow-up was 29.5 months (17.4–62 months). Males were 55.8 % and 57.7 % with average age of 64.5 and 65.9 years, ECOG 2 was detected in 15.4 % and 8.5 % of patients. Other characteristics were also comparable: CPS > 10 69.2 % and 19.7 % (p = 0.0001), MSI 26.2 % and 4.9 % (p = 0.009), 2nd lines and further treatment were received by 36.5 % and 69.3 % (p = 0.0001), respectively.

Results: in the entire population PFS was 7.9 months and 6.4 months (HR 0.46; 95 % CI 0.32–0.67, p = 0.0001), and OS was 17.3 months and 14.6 months (HR 0.71; 95 % CI 0.49–1.04, p = 0.076), respectively. The univariate analysis showed that only 1 prognostic factor for survival — the number of organs with metastases. In accordance with this, in case of the presence of metastases in 1–2 organs the use of ICI had an advantage in terms of PFS (p = 0.051 and p = 0.001), while in case of 3 or more organs involved there was no advantage (p = 0.62). Assessing the effect of the CPS level in patients with MSS phenotype, it was shown that at CPS0–9 there was no advantage in PFS (6.1 months and 6.9 months, p = 0.7) and OS (8.8 months and 14.9 months, p = 0.39). With CPS > 10, an advantage was noted when adding ICI for PFS (9.9 months and 4.4 months, p = 0.0001), and OS 18.2 months and 12.1 months (p = 0.23). However, the results did not differ at the CPS level > 50. When evaluating patients with MSI, we demonstrated that with a median PFS of 6.6 months and 5.2 months, respectively (HR 0.48; 95 % CI 0.17–1.4; p = 0.165), the median OS in patients who received ICI with or without CT was significantly higher — 24.3 months and 11.1 months, respectively (HR 0.4; 95 % CI 0.13–1.21; p = 0.11).

Conclusions: the use of ICI in the first line therapy for metastatic gastric cancer (compared with CT alone) increases the proportion of patients living without progression for 12 months or more, and the overall survival rate was also increased by more than 2 times. The threshold level of CPS for ICI assignment needs to be > 10. The relationship between the effectiveness of immunotherapy and PD-L1 expression in gastric cancer with MSI tumors requires further study in a larger sample of patients. Information at the CPS level, the presence of MSI and HER2 / neu should be presented at the time of discussion of treatment tactics at the onset of metastatic disease.

1. Kang Y.K., Kang W.K., Shin D.B., et al. Capecitabine / cisplatin versus 5‑fluorouracil / cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 2009;20(4):666–73. https://doi.org/10.1093/annonc/mdn717

2. Al-Batran S.E., Hartmann J.T., Probst S., et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26(9):1435–42. https://doi.org/10.1200/JCO.2007.13.9378

3. Van Cutsem E., Moiseyenko V.M., Tjulandin S.A., et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24(31):4991–7. https://doi.org/10.1200/JCO.2006.06.8429

4. Al-Batran S.E., Hartmann J.T., Hofheinz R., et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2008;19(11):1882–7. https://doi.org/10.1093/annonc/mdn403

5. Pietrantonio F., Randon G., Lonardi S., et al. Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2‑negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial. J Clin Oncol 2024; suppl 17 (abstr LBA4002). https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA4002

6. Bang Y.J., Van Cutsem E., Feyerislova A., et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2‑positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376(9742):687–697. https://doi.org/10.1016/S0140-6736(10)61121-X

7. Muro K., Chung H.C., Shankaran V., et al. Pembrolizumab for patients with PD-L1‑positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17(6):717–726. https://doi.org/10.1016/S1470-2045(16)00175-3

8. Janjigian Y.Y., Bendell J., E. Calvo, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol 2018;36(28):2836–2844. https://doi.org/10.1200/JCO.2017.76.6212

9. Janjigian Y.Y., Shitara K., Moehler M., et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398(10294):27–40. https://doi.org/10.1016/S0140-6736(21)00797-2

10. Rha S.Y., Wyrwicz L., Weber P.E.Y., et al. KEYNOTE-859 study of pembrolizumab plus chemotherapy for advanced HER2‑negative gastric or gastroesophageal junction (G / GEJ) cancer: Outcomes in the protocol-specified PD-L1-selected populations. J Clin Oncol 2023;41 (suppl 16; abstr 4014)

11. Chao J., Fuchs C.S., Shitara K., et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol 2021;7(6):895–902. https://doi.org/10.1001/jamaoncol.2021.0275

12. Janjigian Y.Y., Ajani J.A., Moehler M., et al. First-Line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3‑year follow-up of the phase III CheckMate 649 trial. J Clin Oncol 2024;42(17):2012–2020. https://doi.org/10.1200/JCO.23.01601