GSK's Jemperli Achieves 82% Complete Response in dMMR Solid Tumors, Enabling Surgery-Free Treatment in 80% of Patients

Recently,GSKIn2025American Association for Cancer Research (AACR) was announced at the annual meeting, itsPD-1InhibitorJemperli（dostarlimab) In2In the clinical trial period, used for treatmentMismatch Repair Deficiency (dMMR) Encouraging results for cancer patients. The analysis shows,After receiving six months of monotherapyAfter treatment with dostarlimab,82% Clinical Complete Response Rate (cCR) Achieved in 117 dMMR Solid Tumor Patients, with 80% Ultimately Exempt from Surgery. This breakthrough data not only pushes the boundaries of immunotherapy applications in early-stage cancer but also marks that the precision treatment model driven by molecular markers is reshaping the traditional tumor treatment paradigm. These results were simultaneously published in The New England Journal of Medicine.This is reportedly the first study to show that immunotherapy can replace surgical treatment for various solid tumors.

Research Background

Tumors with DNA mismatch repair deficiency (dMMR) are characterized by dysfunction in mismatch repair genes within tumor cells, which often leads to high microsatellite instability (MSI-H) and a high mutation burden. These tumors, due to the production of a large number of neoantigens, exhibit high sensitivity to immune checkpoint inhibitors (ICI).

In the treatment of localized (early-stage) tumors, surgical resection has long been regarded as one of the primary curative approaches. However, complications from surgery can significantly impact patients' postoperative quality of life. In recent years, neoadjuvant immunotherapy has gradually emerged, offering a new approach for treating dMMR tumors without the need for surgery.

Study Design

This study, led by Andrea Cercek and others from the Memorial Sloan Kettering Cancer Center in the United States, is a Phase 2 clinical trial investigating neoadjuvant PD-1 monoclonal antibody therapy for locally advanced rectal cancer.

The study enrolled a total of 117 patients with stage Ⅰ to Ⅲ dMMR solid tumors.These patients had various types of tumors, including rectal cancer, colon cancer, gastroesophageal cancer, urothelial carcinoma, hepatobiliary tumors, prostate cancer, endometrial cancer, and small intestine cancer, among others. At the time of enrollment, all patients had tumors that were eligible for curative surgical resection.

The patient received neoadjuvant treatment with the PD-1 monoclonal antibody dostarlimab, with a treatment cycle of once every 3 weeks for a total of 9 cycles. Patients were divided into Cohort 1 (patients with locally advanced rectal cancer) and Cohort 2 (patients with other dMMR solid tumors excluding rectal cancer).

After the completion of treatment, the tumor's response is evaluated based on imaging and endoscopic examination results. If the patient achieves clinical complete remission (CCR), surgery may be avoided, transitioning instead to a non-surgical management approach with close follow-up. If residual lesions remain in the patient, surgical resection of the tumor will be performed according to the standard protocol.

Research Results

In the rectal cancer cohort (Cohort 1),All 49 patients who completed treatment achieved clinical complete remission and initially opted for non-surgical management. During the 12-month follow-up period, 37 rectal cancer patients remained tumor-free, successfully reaching the pre-defined primary endpoint.

Figure 1. Clinical Outcomes

In the non-rectal solid tumor cohort (Cohort 2), 35 out of 54 patients (approximately 65%) who completed neoadjuvant therapy achieved clinical complete response, with 33 patients (61%) opting for non-surgical treatment.

Figure 2. ctDNA clearance in patients with different clinical responses.

Figure A shows the proportion of patients with detectable ctDNA at different time points according to their clinical remission status. Figure B displays the changes in ctDNA levels over time for each patient based on their clinical remission status.

Combined data from the two cohorts show that, among all 103 patients who completed the treatment course,A total of 84 cases (82%) achieved clinical complete remission, and ultimately, 82 patients (80%) successfully avoided surgery.

Follow-up data showed that the 2-year recurrence-free survival rate for all 117 patients was as high as 92%. By subgroup, the 2-year recurrence-free survival rate for rectal cancer patients was 96%, while for other cancer patients, due to the shorter median follow-up time, the estimated 2-year recurrence-free rate was approximately 85%. At the time of analysis, only 5 patients had experienced disease recurrence during follow-up. However, some of these recurrent cases still had salvage opportunities. For example, one patient underwent surgical resection of an isolated metastatic lymph node and was recurrence-free post-surgery; another four recurrent patients were re-treated with PD-1 inhibitors, three of whom achieved complete tumor regression again.

Safety: Well-tolerated, low risk during the surgical window period

Adverse reactions are controllable: 65% are grade 1-2 (rash, fatigue), with only 5% being grade 3 or higher events, and no treatment-related deaths.

Surgical Opportunity Retention: Even in patients for whom immunotherapy is ineffective, a seamless transition to surgery is still possible, with no cases of surgery becoming unfeasible due to treatment delays.

Conclusion and Prospect: A Treatment Revolution from "One-Size-Fits-All" to "Tailor-Made"

This study confirmed that neoadjuvant immunotherapy can spare more than 80% of patients with early-stage dMMR tumors from surgery, while preserving organ function and improving quality of life.

This research achievement not only validates the feasibility of the innovative concept of immunological substitution surgery across various types of solid tumors but also further expands its application scope. It highlights the significant value of dMMR as a "pan-indication" biomarker in oncology, suggesting that early detection of tumors with the dMMR phenotype could potentially shrink or even eliminate tumors through neoadjuvant immunotherapy, thereby avoiding traditional surgery and its associated risks.

References:

1. Ambrosini M, Manca P, Nasca V, et al. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers. Nat Rev Clin Oncol 2025 Apr 3. doi: 10.1038/s41571-025-01015-z (Epub ahead of print).

2.Cercek A, Foote MB, Rousseau B, et al. Nonoperative management of mismatch repair–deficient tumors. N Engl J Med 2025 Apr 28. Doi: 10.1056/NEJMoa2404512 (Epub ahead of print).