76% Complete Response Without Surgery Masks Single-Arm Limits in Tiny dMMR Niche

GSK's Jemperli Achieves 76% Complete Response in Rectal Cancer Trial

GSK announced positive interim results from the phase II AZUR-1 trial for Jemperli (dostarlimab) monotherapy in adults with stage II and III microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) locally advanced rectal cancer. The study showed that 76% of evaluable patients achieved a complete response to dostarlimab alone, with no disease recurrences reported among responders after a median follow-up of over two years. These findings highlight the potential for Jemperli to transform treatment by enabling some patients to avoid standard therapies like chemotherapy, radiation, and surgery, which often carry significant lasting side effects. The data supported the recent US approval of Jemperli for this indication.

• The AZUR-1 trial demonstrated a 76% complete response rate (110/144 evaluable patients) with dostarlimab monotherapy. This included 68% (98/144) achieving a sustained clinical complete response for at least 12 months (cCR12) without surgery, and an additional 12 patients confirmed with pathological complete response after surgery.
• The positive results suggest a paradigm shift in treatment, potentially allowing eligible patients with MSI-H/dMMR locally advanced rectal cancer to avoid debilitating standard treatments such as chemotherapy, radiation, and surgery, thereby preserving organ function and improving quality of life.
• The trial met its primary objective, showing a clinically significant proportion of patients achieved cCR12. At the time of analysis, 47% (54/116) had achieved cCR12 by independent central review, with no disease recurrences observed among responders after a median follow-up exceeding two years.
• The safety profile of dostarlimab in this trial was generally consistent with its established profile across solid tumours. Serious adverse reactions occurred in 20% of patients, with permanent discontinuation due to adverse reactions in 3%, and common adverse reactions including fatigue, rash, diarrhoea, and pruritus.

The Lasting Burden of Current MSI-H/dMMR Rectal Cancer Treatments

Conventional management of locally advanced rectal cancer (LARC) with preoperative radiotherapy, chemotherapy and chemoradiotherapy followed by total mesorectal excision (TME) is associated with a pathological complete response rate of only 10-20%. Distant metastasis remains an unresolved issue, and TME can severely impact quality of life.

• Limited activity of chemoradiotherapy in MSI-H disease: MSI-H was not associated with response to nCRT in patients with rectal cancer, with MSI-H tending to be negatively associated with a good response to nCRT but no statistical significance observed (7.1% vs. 24.1%, P = 0.208). The addition of CRT yielded marginal benefit and may be unnecessary in this radioresistant subgroup.

• Morbidity of radical surgery and demand for preservation: Standard treatment involving TME and, for locally recurrent disease, pelvic exenteration and pelvic re-irradiation to achieve R0 margins carries major functional consequences, with quality of life affected in 80.0% of patients undergoing exenterative surgery, mainly related to urinary infections and/or fistula. The demand for anus preservation and better quality of life increases in recent years.

• Uncertainty in response evaluation for watch-and-wait selection: The cCR and pCR is not always consistent, which occurs more frequent when nCRT is combined with immunotherapy. Evaluating the cCR accurately needs the combination of multiple traditional examinations, new detective methods, such as PET-CT, ctDNA-MRD and various omics studies, and finding accurate biomarkers can help guide risk stratification and treatment decisions.

• Immature and heterogeneous immunotherapy evidence base: Reviews were limited by a small number of mostly single-arm studies with lack of long-term survival outcomes, as well as marked clinical and methodological heterogeneity among included studies. Survival and recurrence data were immature and unsuitable for quantitative pooling, with median follow-up (8-26 months) and disease-free survival exceeded 98% in most cohorts, and longer follow-up, predictive biomarkers, and randomized comparisons with upfront surgery are required before its routine clinical use.

• Toxicity and treatment-related local complications: Grade ≥3 adverse events occurred in 3-34% of patients, with no treatment-related deaths reported, while in other cohorts Grade 3-4 adverse events ranged from 3.9% to 45.2% (MSS) and 0% to 60% (MSI-H). ICI-first can permit curative resection, with risk of local complication from significant treatment response, including four patients who developed a clinically significant treatment-related stricture, with one perforation.

• System requirements for safe nonoperative management: Implementation demands multidisciplinary infrastructure including validated response assessment, intensive surveillance protocols, and equitable access to biomarker testing and salvage surgery. Without these elements, organ preservation risks widening existing disparities.

AZUR-1: Jemperli's Potential to Transform MSI-H/dMMR Rectal Cancer

Recent studies in MSI-H/dMMR locally advanced rectal cancer focus on neoadjuvant PD-1 blockade alone or in combination, aiming to maximize complete response and enable organ preservation. Efficacy signals show high complete response rates with manageable toxicity, while larger prospective trials are evaluating durability and long-term outcomes.

• AZUR-1 (NCT05723562) – dostarlimab monotherapy: Multicenter, open-label, nonrandomized, single-arm phase 2 study enrolling approximately 150 patients across 10 countries with previously untreated stage II/III dMMR or microsatellite instability-high (MSI-H) phenotype. Intervention is dostarlimab 500 mg administered intravenously every 3 weeks for 9 cycles. Primary endpoint is cCR by independent central review (ICR) at 12 months, with key secondary endpoints including cCR by ICR at 24 and 36 months, and 3-year event-free survival by investigator assessment, plus organ preservation rate at 3 years and disease-specific survival and overall survival at 5 years.

• Multicenter cohort study of neoadjuvant anti-PD-1 monotherapy with watch-and-wait – PD-1 inhibitor as initial nIT: Twenty patients who received a PD-1 inhibitor as initial nIT were examined, with 18 patients (90%) achieving complete response (CR) after a median of 7 nIT cycles, including 11 with pCR after surgery and 7 who chose a WW strategy after evaluation as cCR or near-cCR. Neither group had a case of LR or DM, and the 2-year DFS and OS in each group was 100%, with median follow-up times of 25.0 months. The two groups had similar incidences of irAEs (P=0.627), while in the pCR group 2 patients (18.2%) had permanent colostomy, 3 (27.3%) had temporary ileostomy, and 2 (18.2%) had srAEs.

• Prospective, multicenter, phase Ib study – sintilimab plus hypofractionated radiotherapy: Patients with MSI-H/dMMR LARC will receive hypofractionated radiotherapy (5 Gy × 5) and three cycles of sintilimab 200 mg IV every 2 weeks, with radical surgery performed 6-8 weeks after radiotherapy. Primary endpoint is adverse reaction after neoadjuvant treatment and perioperative complications, with secondary endpoints including pathological response rate, complete resection rate, and quality of life.

• Preoperative chemoradiotherapy plus nivolumab – CRT followed by consolidation nivolumab and surgery: Phase I/II evaluation of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery in MSS and MSI-H LARC. A pathologic complete response (pCR) was centrally confirmed in 60% (3/5) of the exploratory MSI-H cohort, while immune-related severe adverse events were observed in 3 patients, with no treatment-related deaths observed.

Jemperli's Expanding Role and PD-1 Mechanism in Oncology

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, is being trialled beyond locally advanced rectal cancer in endometrial cancer, diverse mismatch repair deficient solid tumors, and resectable colon cancer. Intervention models range from nonrandomized single-arm monotherapy to a randomized perioperative comparison with standard of care.

• Mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment: assessed in GARNET (NCT02715284), a non-randomized, multicenter, open-label, multi-cohort trial of dostarlimab monotherapy; patients received 500 mg intravenously every three weeks for four doses, then 1000 mg intravenously every six weeks until disease progression or unacceptable toxicity.

• dMMR colorectal cancer and other dMMR solid tumors: assessed in the GARNET phase 1, open-label, single-group, multicenter study in patients with advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors; the efficacy population included 327 patients with 105 patients (32.1%) with dMMR colorectal cancer and 81 patients (24.8%) with other dMMR tumor types; patients received 500 mg intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.

• Mismatch repair proficient (MMRp)/microsatellite stable (MSS) endometrial cancer: assessed in GARNET cohort A2 as a single-arm, open-label, phase I trial of intravenous dostarlimab; patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression.

• Previously untreated, pathologically confirmed, radiologically evaluable T4N0 or Stage III resectable dMMR/MSI-H colon adenocarcinoma: evaluated in AZUR-2 (NCT05855200), an ongoing global, Phase III, open-label, randomized study of perioperative dostarlimab monotherapy compared with standard of care (SoC) (adjuvant chemotherapy or surveillance); patients are randomized 2:1 to receive neoadjuvant dostarlimab 500 mg every 3 weeks (4 cycles), followed by surgery, then adjuvant dostarlimab 1000 mg every 6 weeks (6 cycles), or to receive immediate surgery followed by SoC.

Dostarlimab: Reshaping Rectal Cancer Treatment with Organ Preservation

The recent positive interim data from the AZUR-1 trial for dostarlimab in stage II and III MSI-H/dMMR locally advanced rectal cancer marks a pivotal moment for patients and clinicians alike. The reported 76% complete response rate, coupled with over two years of recurrence-free follow-up among responders, paints a compelling picture of immunotherapy's potential to fundamentally alter the treatment landscape for this specific patient population. This efficacy is particularly significant given the profound morbidity associated with current standard-of-care treatments, which often involve extensive chemotherapy, radiation, and surgery, frequently leading to permanent ostomies and other life-altering side effects.

The strategic implications for GSK and the broader oncology field are substantial:

• Dostarlimab is poised to become a front-line, organ-preserving option, potentially allowing a significant subset of patients to avoid invasive surgery and its associated complications, thereby enhancing their quality of life.

• This success reinforces the value of precision medicine in oncology, demonstrating how targeting specific tumor biomarkers like MSI-H/dMMR can yield exceptional clinical outcomes and establish new therapeutic benchmarks.

However, as with any transformative therapy, important considerations remain. The AZUR-1 trial, while impressive, is a single-arm study, meaning direct comparative data against conventional treatments are still needed to fully contextualize its benefits. Furthermore, while initial follow-up is promising, the long-term durability of these complete responses and the optimal selection of patients for a watch-and-wait strategy will require continued investigation. The systematic review of neoadjuvant immune checkpoint inhibition in dMMR/MSI-H colorectal cancer underscores the need for longer follow-up, predictive biomarkers, and randomized comparisons to fully assess long-term quality of life, toxicity, and cost-effectiveness against established surgical approaches. Moving forward, the integration of dostarlimab into clinical practice will necessitate careful patient selection and ongoing monitoring to ensure sustained benefits and optimal patient outcomes.