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Sincerely invite attention to “Frontline of Immunotherapy for Gastrointestinal Cancer!“
Professor Xu Tongpeng
MD, Associate Chief Physician of Oncology at Jiangsu Provincial People’s Hospital, Associate Professor, Master’s Supervisor
Member of the Oncology Branch of Jiangsu Medical Association
Member of the Multi-primary and Unknown Primary Tumor Committee of Jiangsu Anti-Cancer Association
Deputy Leader of the Clinical Precision Medicine Translational Medicine Group of Jiangsu Physician Association
Secretary of the Jiangsu Anti-Cancer Alliance
Published over 20 SCI-indexed papers as the first/corresponding author (including co-first authors), three of which have an IF > 10. Awarded multiple honors including the Third Prize of the Chinese Medical Science and Technology Award, Second Prize of Jiangsu Provincial Science and Technology Award, and First Prize of Jiangsu Provincial New Technology Introduction Award; Principal Investigator of two National Natural Science Foundation projects and two Jiangsu Provincial Natural Science Foundation projects.
Research direction: Immunotherapy, targeted therapy, and basic and clinical research of novel CAR-T cell immunotherapy for malignant tumors
Tislelizumab Combined with Anlotinib and Chemotherapy (XELOX) for Advanced Gastric Cancer: Preliminary Results of a Single-Arm, Open-Label Phase I/IIa Trial (TALENT Study)[1]
【Research Background and Purpose】
1. PD-1 inhibitors combined with chemotherapy are one of the standard regimens for first-line gastric/gastroesophageal junction adenocarcinoma (GC/GEJC).
2. VEGFR can normalize blood vessels, altering the tumor microenvironment, and has a synergistic effect with PD-1 inhibitors.
3. The study aims to explore the safety and efficacy of Tislelizumab combined with Anlotinib and XELOX as first-line treatment for advanced GC/GEJC.
【Research Method】 Prospective, multi-center, phase I/IIa study.
Plan to enroll 9 patients in the phase I dose escalation stage and 57 patients in the phase IIa dose expansion stage.
The study aims to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety of Anlotinib at doses of 8 mg, 10 mg, or 12 mg combined with XELOX and Tislelizumab. The MTD will apply to all patients in phase II.
The primary endpoint is MTD and ORR. Secondary endpoints include DCR, DoR, PFS, OS, and safety. Exploratory endpoints assess the relationship between efficacy and the expression of biomarkers (including PD-L1, microsatellite instability, and genomic stability).
【Research Results】From March 2021 to August 2022, 38 patients were enrolled (including 9 patients in the dose escalation study).No DLT occurred during the dose escalation phase, and 12 mg Anlotinib was recommended for the phase II trial.
The median age of patients was 67 years, with 44.74% (17 cases) having gastroesophageal junction cancer and 31.58% (12 cases) being poorly differentiated.
Among 29 analyzable patients, 2 achieved CR, 20 achieved PR, with an ORR of 75.9% (95% CI: 57.9%-87.8%), and a DCR of 100%. Three patients underwent surgical resection after treatment.
32 patients (84.21%) experienced at least one TRAE, with 7 patients (18.42%) experiencing at least one grade 3/4 TRAE.
Anemia (15 cases, 39.47%), leukopenia (12 cases, 31.58%), and fatigue (10 cases, 26.32%) were the most common TRAEs.
The overall safety was manageable.
【Research Conclusion】Preliminary results indicate that the Tislelizumab combined with Anlotinib and XELOX regimen shows good anti-tumor activity and manageable safety for first-line treatment of advanced gastric cancer.
Expert Commentary
For patients with HER2-negative and PD-L1 CPS ≥5, immunotherapy combined with chemotherapy has become the standard treatment for advanced first-line gastric/gastroesophageal junction adenocarcinoma. Based on the current published results of the Checkmate649 study, Rationale305 study, and Orient16 study, the OS for positive PD-L1 expressing populations in Asia/China is about 15.5 to 19.3 months, with an overall OS improvement of about 6 months compared to chemotherapy alone, and ORR not exceeding 60%. However, for PD-L1 negative patients, the benefits of immunotherapy combined with chemotherapy are relatively limited.
The TALENT study added anti-angiogenic drugs to the base of immunotherapy combined with chemotherapy, achieving an ORR of 76%, which has improved the ORR of advanced first-line GC/GEJC populations to a certain extent, especially for PD-L1 negative patients, achieving unexpected efficacy, which is a high ORR data reported in current advanced first-line treatments.
Additionally, among patients achieving PR, three underwent conversion therapy, maximizing tumor burden reduction for longer survival, providing a good reference value for the treatment model of gastric cancer conversion therapy. In terms of safety results, the safety of this study is also manageable. This study provides a new treatment option for HER2 and PD-L1 negative populations.
Zolbetuximab Combined with mFOLFOX6 for Claudin-18.2+ (CLDN18.2+)/HER2− Locally Advanced (LA) Unresectable or Metastatic Gastric or Gastroesophageal Junction (mGC/GEJC) Adenocarcinoma: Primary Results from Phase 3 SPOTLIGHT Study[2]
【Research Background】
1. CLDN18.2 is an important protein in normal tissue tight junctions, usually expressed in gastric mucosal cells and retained in GC/GEJC adenocarcinoma. CLDN18.2 may be exposed on the surface of GC/GEJC adenocarcinoma cells, making it a promising target.
2. In the phase IIb FAST study, EOX±Zolbetuximab prolonged survival in patients with high CLDN18.2 expression in tumor cells.
【Research Design】Global, randomized, double-blind, placebo-controlled, phase III clinical trial.
【Research Results】As of September 2022, the Asian population accounted for 30% of the baseline data, with GC accounting for about 75% and intestinal type about 25%. Among them, 41/311 (13.2%) of assessable patients had tumor PD-L1 CPS ≥5.
1. Primary endpoint PFS: Median follow-up time was 12.94 months (Zolbetuximab) vs 12.65 months (Placebo).
2. Key secondary endpoint OS: Median follow-up time was 22.14 months (Zolbetuximab) vs 20.93 months (Placebo).
3. Secondary endpoint ORR: 60.7% (53.72%-67.30%) vs 62.1% (55.17%-68.66%), with similar efficacy rates between treatment groups.
4. Safety:
【Research Conclusion】
1. The PFS and OS of the Zolbetuximab+mFOLFOX6 treatment group showed statistically and clinically significant improvement:
One of the longest mOS in phase III trials for patients with LA unresectable or mGC/GEJC adenocarcinoma; survival benefits were observed in most subgroups.
2. Zolbetuximab+mFOLFOX6 demonstrated tolerable and manageable safety:
Safety was consistent with previous studies of Zolbetuximab and mFOLFOX6; nausea and vomiting were the most common TEAEs, mainly occurring in the first cycle of Zolbetuximab.
3. Zolbetuximab+mFOLFOX6 is a new potential standard treatment for CLDN18.2+/HER2- locally advanced unresectable or mGC/GEJC adenocarcinoma patients.
In the treatment of advanced gastric cancer, the current standard first-line regimens revolve around the ToGA study, Checkmate649 study, and Orient16 study results, distinguishing between HER2 and PD-L1 expression to select targeted combination chemotherapy or immunotherapy combination chemotherapy. Recent studies have found that CLDN18.2 is specifically highly expressed in gastric cancer, and previous phase I/II studies suggest that patients with advanced gastric cancer with high CLDN18.2 expression can benefit from this targeted drug.
The results of the phase III clinical trial of Zolbetuximab combined with mFOLFOX6 for recurrent or metastatic CLDN18.2 positive and HER2 negative gastric or gastroesophageal junction adenocarcinoma achieved expected goals, with improvements in both PFS and OS, with a 2-month increase in PFS and nearly 3-month increase in OS compared to the chemotherapy group; safety showed significant increases in severe nausea, appetite loss, and fatigue.
It is noteworthy that the OS of the control group in this study was longer than previously reported phase III study results for advanced first-line gastric cancer chemotherapy and immunotherapy, which may be related to the selection of enrollment groups. In terms of overall safety, compared to other advanced gastric cancer studies, gastrointestinal toxicity has increased. For gastric cancer, a gastrointestinal tumor with poor prognosis, whether the increase in gastrointestinal toxicity will further make patients with original gastrointestinal discomfort intolerable remains a long-term observation and exploration issue. However, we see that the study achieved positive results for the primary endpoint, indicating that CLDN18.2 is a promising target for the treatment pattern of advanced gastric cancer.
At the ASCO-GI conference, we also discovered the layout of other CLDN18.2 targeted drugs + immunotherapy + chemotherapy combinations in advanced GC/GEJC[3]. Similar combinations of targeted + immune + chemotherapy, such as the Keynote811 study, also achieved good results. As immunotherapy + chemotherapy becomes the mainstream of first-line standard treatment, whether various combinations can succeed remains to be seen.
Cabozantinib Combined with Pembrolizumab for ICI-Refractory Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma[4]
【Research Background and Purpose】
1. The majority of patients have a PFS rate of only 5% after 6 months of monotherapy following progression on systemic therapy, including immune checkpoint inhibitors (ICI).
2. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor, and previous studies have shown that Cabozantinib can modulate immunosuppression in the tumor immune microenvironment.
3. This investigator-initiated single-arm, two-stage, single-center, phase II study aims to evaluate the efficacy and safety of Cabozantinib combined with Pembrolizumab for ICI-refractory metastatic gastric/gastroesophageal junction adenocarcinoma.
【Research Design】
【Research Results】25 patients from different countries with gastric/gastroesophageal junction cancer were enrolled in the study.
The median follow-up time was 23.1 months (5.9 months – 34 months), with 6 patients (24%) having a PFS ≥ 6 months, achieving the primary study endpoint. The median PFS was 2.5 months (95% CI: 1.7-5.6). The median OS was 5.5 months (95% CI: 3.1-11.3). Two patients completed the study treatment (24 months) and achieved disease-free status.
Safety:
The most common treatment-related AE was diarrhea (28%), fatigue (20%), and hypertension (16%), with a ≥ grade 3 treatment-related AE incidence of 12%, and no grade 5 adverse events occurred.
Among 18 patients, the most common immune-related AE events were skin itching and thyroiditis. Three patients experienced grade 3 immune-related adverse events, all alleviated by high-dose steroids without affecting surgery.
【Research Conclusion】
1. Cabozantinib combined with Pembrolizumab shows promising clinical benefits in ICI-refractory advanced gastric cancer.
2. The primary endpoint of this study has been met, with a 6-month PFS rate of 24% for Cabozantinib combined with Pembrolizumab.
3. This treatment regimen did not present new safety signals, and safety was good.
Expert Commentary
There are limited drug treatment options for second-line and beyond in advanced gastric cancer, and in the context of immunotherapy combined with chemotherapy, how to choose treatment options after immunotherapy resistance and how to treat HER2+ patients after trastuzumab resistance pose significant challenges for clinicians.
In the study, Cabozantinib was used in combination with PD-1 treatment for the resistant population, and the results showed a 6-month PFS rate of 24%, achieving the primary study endpoint. Furthermore, two patients achieved over 2 years of long PFS using Cabozantinib combined with immunotherapy in the context of immune resistance. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor, and previous studies have shown that it can modulate immunosuppression and reverse immune resistance in the tumor immune microenvironment. This study is a small sample investigator-initiated single-arm, two-stage, phase II study that has yielded promising results, and further studies with larger sample sizes are needed to provide new treatment options for gastric cancer patients with immune therapy resistance.
Literature Source (2023 ASCO-GI):
[1]Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: Preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study).(Poster Session; Abstract No: 396; NCT04963088)
[2]Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study(Oral Abstract Session; Abstract No: LBA292; NCT03504397)
[3]TST001+nivolumab+XELOX G/GEJ (TST001-1002). (TPS476).
[4]Phase 2 study of cabozantinib (cabo) and pembrolizumab (pembro) in metastatic gastric/gastroesophageal adenocarcinoma (mGEA) refractory to immune checkpoint inhibitors (ICIs). (Poster; Abstract No: 345; NCT04164979)
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Previous Highlights
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