Toripalimab + Chemo in Gastric & GEJ Cancer: NEOSUMMIT-01 Phase Trial Insights

Abstract

Locally advanced gastric and gastroesophageal junction (GEJ) cancers present significant treatment challenges despite standard perioperative chemotherapy regimens. The addition of immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) inhibitors, to these regimens is currently under investigation for its potential to improve patient outcomes. The NEOSUMMIT-01 phase 2 trial aimed to evaluate the efficacy and safety of combining the PD-1 inhibitor toripalimab with standard chemotherapy (SOX/XELOX) compared to chemotherapy alone in patients with resectable gastric or GEJ cancer. Results indicate that the combination of toripalimab and chemotherapy significantly improves the rate of pathological complete response and near-complete response compared to chemotherapy alone. The safety profile of the combination treatment is comparable to that of chemotherapy alone, suggesting that toripalimab can be a valuable addition to perioperative treatment strategies.

Introduction

Locally advanced gastric and gastroesophageal junction (GEJ) cancers pose significant therapeutic challenges, often necessitating aggressive treatment strategies. Despite advancements in therapeutic approaches, these cancers frequently present with a poor prognosis due to their tendency for early metastasis and resistance to conventional treatments. Perioperative chemotherapy has been a cornerstone of treatment for these patients, aimed at reducing tumor size and addressing micrometastatic disease before surgical resection.

Standard chemotherapy regimens for gastric and GEJ cancers typically include combinations such as SOX (S-1 plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin). These regimens have demonstrated efficacy in improving resectability and survival rates. However, a substantial proportion of patients still experience disease recurrence or progression, highlighting the need for novel therapeutic strategies.

In recent years, the integration of immune checkpoint inhibitors into cancer treatment regimens has shown promise in enhancing therapeutic outcomes. Programmed cell death 1 (PD-1) inhibitors, such as toripalimab, have been shown to improve overall survival and progression-free survival in various malignancies. The potential of these agents to augment the effectiveness of perioperative chemotherapy in gastric and GEJ cancers is an area of active research.

The NEOSUMMIT-01 phase 2 trial was designed to evaluate the efficacy and safety of combining toripalimab with standard chemotherapy regimens in patients with resectable gastric and GEJ cancers. This trial aims to provide insights into whether the addition of a PD-1 inhibitor can improve pathological response rates compared to chemotherapy alone and to assess the safety of this combination therapy.

Literature Review

Standard Perioperative Therapy for Gastric and GEJ Cancer

Gastric cancer remains a significant global health issue, with high morbidity and mortality rates. For patients with locally advanced gastric or GEJ cancers, the standard treatment approach involves perioperative chemotherapy, followed by surgical resection. The goals of perioperative chemotherapy are to reduce tumor burden, address potential micrometastatic disease, and improve surgical outcomes. Regimens such as SOX and XELOX have become standard due to their efficacy in reducing tumor size and improving resectability.

Research into perioperative chemotherapy has focused on optimizing treatment regimens to improve outcomes. Studies have demonstrated that patients receiving perioperative chemotherapy have better survival outcomes compared to those receiving surgery alone. However, despite these advances, the survival rates for patients with locally advanced gastric and GEJ cancers remain suboptimal, underscoring the need for additional therapeutic strategies.

Immune Checkpoint Inhibitors and Their Mechanism of Action

Immune checkpoint inhibitors, particularly those targeting the PD-1/PD-L1 pathway, have revolutionized the treatment of various cancers. These inhibitors work by blocking the interaction between PD-1 receptors on immune cells and PD-L1 on tumor cells, thereby preventing the suppression of the immune response against cancer cells. This mechanism allows the immune system to better recognize and attack tumor cells.

PD-1 inhibitors, such as pembrolizumab, nivolumab, and toripalimab, have shown significant clinical efficacy in several cancers, including melanoma, non-small cell lung cancer, and bladder cancer. These agents have been shown to improve overall survival and progression-free survival in patients with advanced cancers who have not responded adequately to conventional treatments.

Combination of PD-1 Inhibitors with Chemotherapy

Combining PD-1 inhibitors with chemotherapy represents a promising approach to enhance therapeutic efficacy. Chemotherapy can induce immunogenic cell death, leading to the release of tumor-associated antigens and enhancing the immune system’s ability to target cancer cells. The addition of PD-1 inhibitors can further potentiate this immune response by preventing the immune suppression commonly associated with tumors.

Several studies have explored the combination of PD-1 inhibitors with chemotherapy in various cancer types. For instance, the KEYNOTE-021 trial demonstrated that the addition of pembrolizumab to chemotherapy improved progression-free survival in patients with non-small cell lung cancer. Similarly, the combination of nivolumab with chemotherapy has shown promising results in patients with gastric cancer, highlighting the potential benefits of this approach in other malignancies as well.

Toripalimab in Gastric Cancer

Toripalimab, a humanized PD-1 monoclonal antibody, has shown promising results in the treatment of various cancers. It has been approved for use in several indications, including head and neck squamous cell carcinoma and nasopharyngeal carcinoma. Toripalimab’s efficacy in gastric cancer is an area of ongoing research, with trials investigating its potential benefits when combined with standard chemotherapy regimens.

Preliminary studies have suggested that toripalimab may enhance the efficacy of chemotherapy by improving the rate of pathological response and overall survival in patients with advanced gastric cancer. The NEOSUMMIT-01 trial specifically aims to evaluate the benefits of combining toripalimab with standard chemotherapy regimens (SOX/XELOX) in patients with locally advanced gastric and GEJ cancers.

Safety and Tolerability of PD-1 Inhibitors in Combination Therapy

The safety profile of PD-1 inhibitors is generally favorable, with most adverse effects being manageable and reversible. Common side effects include immune-related adverse events such as pneumonitis, colitis, and hepatitis. The combination of PD-1 inhibitors with chemotherapy may introduce additional considerations, such as increased risk of overlapping toxicities or enhanced immune-related adverse events.

Studies evaluating the safety of combining PD-1 inhibitors with chemotherapy have generally reported manageable safety profiles, with no significant increase in severe adverse events compared to chemotherapy alone. The NEOSUMMIT-01 trial contributes to this body of evidence by assessing the safety of adding toripalimab to chemotherapy in patients with locally advanced gastric and GEJ cancers.

Conclusion

The integration of PD-1 inhibitors like toripalimab into perioperative chemotherapy regimens represents a promising advancement in the treatment of locally advanced gastric and GEJ cancers. The NEOSUMMIT-01 phase 2 trial provides valuable evidence supporting the efficacy of this combination approach, demonstrating a significant improvement in pathological response rates compared to chemotherapy alone. As ongoing research continues to explore the full potential of immunotherapy in the perioperative setting, these findings contribute to the evolving landscape of gastric cancer treatment and highlight the importance of combining targeted therapies to enhance patient outcomes.

Methodology

Study Design

The NEOSUMMIT-01 trial was a multicenter, open-label, randomized phase 2 clinical trial designed to evaluate the efficacy and safety of combining the PD-1 inhibitor toripalimab with standard chemotherapy in patients with locally advanced gastric or gastroesophageal junction (GEJ) cancer. The study was conducted across 66 hospitals in China from December 20, 2016, to August 9, 2022. The trial's registration number on ClinicalTrials.gov is NCT04250948.

Participants

The trial enrolled patients with histologically confirmed gastric or GEJ cancer staged as cT3-4aN+M0, which indicates resectable disease with local advancement but no distant metastases. Eligibility criteria required patients to be 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Exclusion criteria included previous treatment with PD-1/PD-L1 inhibitors or other immunotherapies, and severe concurrent illnesses.

A total of 108 patients were randomized into two groups: the toripalimab plus chemotherapy group (n = 54) and the chemotherapy alone group (n = 54). Randomization was achieved using a computer-generated randomization sequence, and participants were assigned in a 1:1 ratio to receive either the combination therapy or standard chemotherapy.

Interventions

The intervention for the toripalimab plus chemotherapy group included three preoperative cycles of chemotherapy with SOX (S-1 plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin), followed by the addition of toripalimab, administered every 3 weeks, for a total of five cycles. After surgery, patients continued with toripalimab monotherapy for up to 6 months. The chemotherapy alone group received the same three preoperative cycles of SOX/XELOX, followed by a continuation of the same regimen for a total of five cycles.

Endpoints

The primary endpoint of the study was the pathological complete response (pCR) or near-complete response rate, measured by tumor regression grade (TRG) 0/1. pCR was defined as the absence of residual invasive cancer in the resected specimen, and TRG 0/1 indicated minimal residual disease. Secondary endpoints included overall survival, progression-free survival, surgical morbidity and mortality, and treatment-related adverse events.

Safety Assessments

Safety was assessed through regular monitoring of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Both groups underwent safety assessments at every cycle and during follow-up visits.

Results

Patient Demographics

Of the 108 patients enrolled, the median age was 62 years, with a male predominance (approximately 70%). Baseline characteristics such as ECOG performance status, tumor stage, and histological subtype were comparable between the two groups.

Pathological Response

The primary endpoint analysis showed that the toripalimab plus chemotherapy group achieved a higher pathological complete response rate compared to the chemotherapy alone group. Specifically, 44.4% of patients in the toripalimab group achieved TRG 0/1, compared to 20.4% in the chemotherapy-only group (risk difference 22.7%; 95% CI: 5.8%-39.6%; P = 0.009). Additionally, the proportion of patients achieving pCR (ypT0N0) was 22.2% in the toripalimab group versus 7.4% in the chemotherapy-alone group (P = 0.030).

Safety and Tolerability

Regarding safety, the incidence of grade 3-4 adverse events was comparable between the two groups. In the toripalimab plus chemotherapy group, 35.2% of patients experienced severe adverse events compared to 29.6% in the chemotherapy alone group. Surgical morbidity was slightly lower in the toripalimab group (11.8%) compared to the chemotherapy group (13.5%). Mortality rates were similar between the groups, with 1.9% in the toripalimab group and 0% in the chemotherapy-only group.

Overall Survival and Progression-Free Survival

Overall survival (OS) and progression-free survival (PFS) data were not yet fully mature at the time of analysis. However, early indications suggest that patients in the toripalimab plus chemotherapy group may have improved OS and PFS compared to those receiving chemotherapy alone.

Discussion

Efficacy of Toripalimab Plus Chemotherapy

The results of the NEOSUMMIT-01 trial indicate that combining toripalimab with standard chemotherapy significantly improves the pathological response rates in patients with locally advanced gastric and GEJ cancers. This finding is consistent with previous research suggesting that PD-1 inhibitors can enhance the effectiveness of chemotherapy by augmenting the immune response against tumor cells.

The improved TRG 0/1 and pCR rates observed in the toripalimab group suggest that the addition of toripalimab may lead to better tumor regression and a higher likelihood of complete pathological remission. These results are promising, as achieving a pCR is often associated with improved long-term survival outcomes.

Safety Profile

The safety profile of toripalimab plus chemotherapy was comparable to chemotherapy alone, with similar rates of severe adverse events and surgical complications. This suggests that the addition of toripalimab does not introduce significant additional risks, making it a feasible option for incorporation into standard treatment regimens.

Comparison with Previous Studies

The findings from NEOSUMMIT-01 align with results from other studies exploring the combination of PD-1 inhibitors with chemotherapy in various cancers. For example, the KEYNOTE-062 and CheckMate-649 trials demonstrated the potential benefits of combining PD-1 inhibitors with chemotherapy in non-small cell lung cancer and gastric cancer, respectively.

Challenges and Considerations

While the results are encouraging, several challenges remain. The heterogeneity of response among patients highlights the need for further research to identify biomarkers that predict which patients are most likely to benefit from the addition of PD-1 inhibitors to chemotherapy. Additionally, long-term survival data and quality-of-life assessments will be crucial to fully understand the benefits and risks of this treatment approach.

Future Prospects

Optimizing Combination Therapy

The integration of PD-1 inhibitors like toripalimab into standard chemotherapy regimens represents a significant advancement in treating locally advanced gastric and gastroesophageal junction (GEJ) cancers. As the field evolves, optimizing combination therapy will be key to maximizing its benefits. Future research should focus on refining the dosage and scheduling of toripalimab to enhance its efficacy while minimizing potential side effects.

Personalized Medicine

Personalized medicine aims to tailor treatments based on individual patient characteristics, including genetic and molecular profiles. Identifying biomarkers that predict which patients are most likely to benefit from PD-1 inhibitors could lead to more targeted and effective treatment strategies. Advances in genomic and proteomic technologies are expected to provide valuable insights into patient selection and response prediction.

Integration with Emerging Therapies

Combining PD-1 inhibitors with other emerging therapies, such as novel targeted agents or additional immunotherapies, may offer synergistic effects and further improve patient outcomes. Research into the use of combination strategies involving other immune checkpoint inhibitors or agents that modulate the tumor microenvironment could provide new avenues for enhancing treatment efficacy.

Long-Term Follow-Up

Long-term follow-up studies are crucial to assess the durability of responses achieved with toripalimab and chemotherapy. Monitoring patients for long-term survival, recurrence rates, and quality of life will provide a more comprehensive understanding of the benefits and limitations of this treatment approach. Continued collection of data will help to refine treatment protocols and improve patient management.

Global and Diverse Populations

Expanding research to include diverse populations across different geographic regions will help determine the generalizability of the findings. Variations in genetic, environmental, and lifestyle factors may influence treatment outcomes and safety profiles. Multinational and multicentric trials can provide a more comprehensive understanding of how combination therapies perform across different patient populations.

Health Economics and Implementation

Assessing the cost-effectiveness of combining toripalimab with chemotherapy is essential for its broader implementation. Health economic analyses will help determine the economic viability of this treatment strategy compared to standard therapies. Understanding the cost-benefit ratio and potential impact on healthcare resources will guide decision-making and policy development.

Patient-Centric Approaches

Incorporating patient perspectives into research and treatment development is vital. Future studies should include patient-reported outcomes to evaluate the impact of treatment on quality of life and patient satisfaction. Engaging patients in the research process and considering their preferences and concerns can enhance the overall treatment experience and outcomes.

Regulatory and Clinical Practice Guidelines

As evidence accumulates, regulatory agencies and clinical practice guidelines will need to be updated to reflect the latest findings. The inclusion of toripalimab in treatment guidelines will depend on the robustness of the clinical data and its demonstrated benefits in improving patient outcomes. Ongoing dialogue between researchers, clinicians, and regulatory bodies will ensure that new treatment options are effectively integrated into clinical practice.

Conclusion

The NEOSUMMIT-01 trial offers promising insights into the efficacy and safety of combining toripalimab with standard chemotherapy for locally advanced gastric and GEJ cancers. The trial's findings highlight the potential benefits of this combination in improving pathological response rates while maintaining a manageable safety profile. As the field continues to evolve, further research and long-term follow-up will be crucial in validating these results and optimizing treatment strategies. By addressing key areas such as personalized medicine, emerging therapies, and global diversity, future studies can build on these findings to enhance patient care and treatment outcomes in gastric and GEJ cancers.

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