Due to the aggressive nature of gastric cancer, most patients present with advanced inoperable malignancy. In the setting of relapsed, refractory, or metastatic gastric cancer, treatment options generally consist of combination chemotherapy regimens, agents directed at human epidermal growth factor receptor 2 (HER2), and radiation therapy. Unfortunately, these treatment options rarely achieve a durable response.1 Advances in understanding gastric cancer pathogenesis, however, have translated into new therapeutics targeting immune escape mechanisms in cancer and exploration of treatments combining biologics with chemotherapy. At the European Society for Medical Oncology (ESMO) 2021 virtual congress, results were presented from trials investigating new treatments for advanced gastric cancer and gastroesophageal junction (GEJ) cancer. Summarized below are selected studies presented, including the first second-line study of trastuzumab deruxtecan in Western patient populations, sintilimab as a potential first-line treatment, therapy adding ipilimumab or FOLFOX (folinic acid, fluorouracil, and oxaliplatin) to combination treatment with nivolumab and trastuzumab, and a computed tomography (CT)-based radiomics nomogram for predicting clinical response to treatment with programmed death-1 (PD-1) inhibitors in patients with advanced gastric cancer. The study design, patient characteristics, and key outcomes for the selected studies are summarized in the Table.
Primary Analysis of a Phase II Single-Arm Trial of Trastuzumab Deruxtecan in Western Patients With HER2-positive Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer Who Progressed on or After a Trastuzumab-Containing Regimen2
Trastuzumab deruxtecan was demonstrated in the DESTINY-Gastric01 study (ClinicalTrials.gov Identifier: NCT03329690) to improve response and overall survival compared with physician’s choice irinotecan or paclitaxel in patients from Japan and Korea with locally advanced or metastatic HER2+ gastric cancer or GEJ cancer who experienced progression on 2 or more lines of therapy. In the current single-arm phase 2 DESTINY-Gastric02 trial (ClinicalTrials.gov Identifier: NCT04014075), researchers reported data from the first second-line study of trastuzumab deruxtecan in Western patients with unresectable or metastatic gastric cancer or GEJ cancer who experienced progression on or after receiving trastuzumab-containing first-line therapy.
In DESTINY-Gastric02, a total of 79 patients from the United States and the European Union who had received a median of 1 prior therapy (range, 1-2 therapies) were treated with trastuzumab deruxtecan 6.4 mg/kg intravenously (IV) every 3 weeks for a median of 4.3 months (range, 0.7-15.9). Median follow-up was 5.7 months (range, 0.7-15.2). The confirmed objective response rate (the primary endpoint) was 38% (95% CI, 27.3-49.6). Complete response and stable disease were seen in 3.8% and 43% of patients, respectively. Grade 3 and higher treatment-emergent adverse events were seen in 50.6% of patients and were associated with dose discontinuation, reduction, or interruption in 15.2%, 24.1%, and 21.5% of patients, respectively.
The data from this study in Western patients and the results from the DESTINY-Gastric01 study in patients from Japan and Korea support trastuzumab deruxtecan as a potential second-line treatment option for patients with advanced gastric cancer or GEJ who have experienced progression on trastuzumab-based therapy.
Sintilimab Plus Chemotherapy Versus Chemotherapy as First-Line Treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (ORIENT-16): First Results of a Randomized, Double-Blind, Phase III Study3
This study compared the efficacy and safety of the PD-1 inhibitor sintilimab in combination with chemotherapy vs placebo plus chemotherapy as first-line treatment for patients with advanced gastric cancer or GEJ adenocarcinoma (ClinicalTrials.gov Identifier: NCT03745170). A total of 650 patients (61% with a combined positive score [CPS] of 5 or greater) with untreated, unresectable locally advanced or metastatic gastric cancer or GEJ adenocarcinoma were randomly assigned 1:1 to receive sintilimab (3 mg/kg and 200 mg, respectively, for body weight <60 kg and ≥60 kg, IV every 3 weeks) or placebo plus chemotherapy (CapeOX: oxaliplatin 130 mg/m2 IV every 3 weeks, up to 6 cycles, and capecitabine 1000 mg/m2 orally twice daily on days 1-14 every 3 weeks) for up to 24 months. The primary endpoint was overall survival (OS) in all patients and in patients with CPS ≥5.
Overall, sintilimab plus chemotherapy was superior to chemotherapy for all the endpoints assessed in all patients and patients with CPS ≥5. Median OS in all patients was, respectively, 15.2 months with sintilimab plus chemotherapy vs 12.3 months with chemotherapy (hazard ratio [HR], 0.766; 95% CI, 0.626-0.936; P =.0090) and in patients with CPS ≥5 was 18.4 vs 12.9 months, respectively (HR, 0.660; 95% CI, 0.505-0.864; P =.0023). Differences in progression-free survival (PFS) outcomes were also statistically significant in favor of sintilimab plus chemotherapy. Similarly, grade ≥3 treatment-related adverse events (TRAE) were similar between both treatment groups (59.8% vs 52.5%, respectively). However, the occurrence of TRAE leading to death was higher with sintilimab plus chemotherapy (1.8%) than with chemotherapy (0.6%).
This interim analysis supports sintilimab in combination with chemotherapy as a potential first-line treatment option for patients with advanced gastric cancer or GEJ adenocarcinoma. The combination provided superior OS and PFS compared with standard chemotherapy regimens, with an acceptable safety profile.
Ipilimumab or FOLFOX in Combination with Nivolumab and Trastuzumab in Previously Untreated HER2 Positive Locally Advanced or Metastatic Esophagogastric Adenocarcinoma: Results of the Randomized Phase II INTEGA trial (AIO STO 0217)4
The addition of PD-1 inhibitors to chemotherapy has been demonstrated to improve outcomes in the first-line treatment of selected patients with advanced or metastatic esophagogastric adenocarcinoma (EGA). This exploratory study compared different immunotherapy regimens in the first-line treatment of 88 HER2+ patients previously untreated for advanced EGA (ClinicalTrials.gov Identifier: NCT03409848). The 44 patients randomly assigned to arm A received a triple-immune-therapy regimen of trastuzumab and nivolumab (240 mg or 1 mg/kg with ipilimumab) combined with ipilimumab (4 × 3 mg/kg every 3 weeks). The 44 patients randomly assigned to arm B received the same trastuzumab and nivolumab regimen but combined with mFOLFOX6. Treatment duration for both arms was up to 12 months. The primary endpoint was an increase in 12-month OS from 55% (with the trastuzumab/chemotherapy regimen, arm B) to 70% with triple immune therapy (arm A) in all patients and in patients with programmed death-ligand 1 (PD-L1) CPS >1 and CPS >5.
The primary endpoint of an increase in OS to 70% at 12 months was reached in arm B but not in arm A in all groups (70% vs 57%) and in patients with PD-L1 CPS >1 vs CPS >5 (70% in arm B vs 54% in arm A). The occurrence of treatment-related grade 3/4 serious adverse events was similar in arm B vs arm A (reported for 15 and 17 patients, respectively).
Combination triple therapy with trastuzumab, nivolumab, and FOLFOX but not with trastuzumab, nivolumab, and ipilimumab improved OS compared with the trastuzumab-plus-chemotherapy regimen. This suggests that the triple combination including FOLFOX can improve survival in the first-line treatment of patients with HER2+ locally advanced or metastatic EGA.
A Radiomics Model for Effective Prediction of the Treatment Benefits of Programmed Cell Death 1 Inhibitors in Advanced Gastric Cancer5
Selecting patients who may benefit from treatment with PD-1 inhibitors is vital in advanced gastric cancer. In this retrospective observational study, the researchers developed an individualized radiomics model to predict the treatment benefits of PD-1 inhibitors in 58 patients with advanced gastric cancer (Chinese Clinical Trial Register: UHCT-IEC-SOP-016-02-03). Pretreatment-enhanced CT imaging data were extracted and an individual radiomics nomogram was constructed based on the imaging data and clinic pathologic risk factors. The clinical utility of the model was evaluated in the training and validation cohorts, and the investigators explored the utility of this model for prediction of patient survival.
Using the model, the researchers found a correlation between the response to treatment with PD-1 and serum carcinoembryonic antigen levels and tumor metastasis site. The model effectively predicted the treatment response to PD-1 inhibitors in both the training cohort (area under curve [AUC], 0.813; 95% CI, 0.803-0.822) and the validation cohort (AUC, 0.750; 95% CI, 0.717-0.782) (P <.01). The model also discriminated between longer PFS of patients with low risk vs high risk of progression.
Predicting response to PD-1 inhibitors using a CT-based radiomics nomogram may guide appropriate treatment decision-making for patients with advanced gastric cancer, with the potential to improve clinical outcomes.
A growing body of research has identified effective management strategies for patients with advanced gastric cancer. Studies of gastric cancer presented at the ESMO 2021 virtual congress included reports on novel agents, new chemotherapy options, and the use of modeling to predict treatment response. One of these studies reported data from the first second-line trial of trastuzumab deruxtecan in Western patients with gastric cancer who experienced progression on or after trastuzumab-containing first-line therapy, and another highlighted the potential of sintilimab in combination with chemotherapy as first-line treatment for advanced gastric cancer. Another important study showed that the triple-agent combination of trastuzumab, nivolumab, and FOLFOX but not trastuzumab, nivolumab, and ipilimumab improved OS compared with trastuzumab plus chemotherapy. In the area of predictive modeling, a radiomics model showed the potential to effectively predict treatment benefits of PD-1 inhibitors in advanced gastric cancer. Looking ahead, emerging novel treatments and strategies hold promise for improved clinical outcomes and quality of life for patients with advanced gastric cancer.
Several study authors declared affiliations with the pharmaceutical industry. Please see the original references for a full list of authors’ disclosures.
- Olnes MJ, Martinson HA. Recent advances in immune therapies for gastric cancer. Cancer Gene Ther. 2021;28(9):924-934. doi:10.1038/s41417-021-00310-y
- Van Cutsem E, Di Bartolomeo M, Smyth E, et al. Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in Western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
- Xu J, Jiang H, Pan Y, et al. Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study. Ann Oncol. 2021;32(suppl 5): S1283-S1346. doi:10.1016/annonc/annonc741
- Stein A, Paschold L, Tintelnot J, et al. Ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive locally advanced or metastatic esophagogastric adenocarcinoma (EGA): Results of the randomized phase II INTEGA trial (AIO STO 0217). Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
- Huang A, Ma H, Bi J, Xiao Y, liang Z, Zhang T. A radiomics model for effective prediction of the treatment benefits of programmed cell death 1 inhibitors in advanced gastric cancer. Ann Oncol. 2021;32(suppl 5):S829-S866. Doi:10.1016/annonc/annonc705
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Reviewed October 2021