Jemperli Eliminated All Signs of Rectal Cancer in Small Clinical Trial, Warranting Further Research

A small clinical trial testing Jemperli (dostarlimab-gxly) in patients with stage 2/3 mismatch repair-deficient (dMMR) locally advanced rectal cancer showed that all patients experienced a clinical complete response, meaning that there was no detectable cancer after treatment.

Findings from the study were presented at the 2022 ASCO Annual Meeting and published in the New England Journal of Medicine.

“No patients have required chemotherapy, radiation or surgery (and) there has been no disease recurrence observed during the follow-up period,” Dr. Andrea Cercek, said in a presentation of the data. “Longer follow-up is certainly required to establish the durability of this treatment. In conclusion we believe these data provide the framework for immunoablative therapies. It highlights the clinical impact of biomarker-driven therapy, in other words of moving precision medicine into early-stage disease.”

Cercek is section head of colorectal cancer and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center in New York, New York, where the trial was conducted.

The median follow-up for the analysis was 6.8 months.

“The majority of our patients (achieve clinical complete response) at six months, but we did have a few at three months as well. (We have) quite a bit of a range from 0.7 to nearly 24 months and all patients remain disease free,” Cercek said.

“Standard of care for T3, T4 or node-positive rectal cancer involves trimodality therapy (consisting of chemotherapy, radiation and surgery),” explained Dr. Kimmie Ng, associate chief of the Division of Gastrointestinal Oncology, director of the Young-Onset Colorectal Cancer Center, codirector of the Colon and Rectal Cancer Center, and director of Translational Research in the Division of Gastrointestinal Oncology at Dana-Farber Cancer Center in Boston, Massachusetts in a discussion of the data.

“However, because components of the standard of care may lead to significant morbidity and quality-of-life issues, many recent studies have tried to eliminate components of the standard of care while still maintaining efficacy,” said Ng, who is also an associate professor of medicine at Harvard Medical School.

Approximately 5% to 10% of rectal cancers are dMMR, which is associated with resistance to chemotherapy. Investigators hypothesized that PD-1 blockade may replace chemotherapy, chemotherapy and radiation, or replace the trimodality approach of chemotherapy, radiation and surgery.

Patients enrolled on the trial received the PD-1 monoclonal antibody Jemperli at 500 mg intravenously every three weeks for six months, equaling nine total cycles. At baseline and through treatment, patients were closely monitored and assessed for response at six weeks, three months and six months. At these key timepoints patients underwent endoscopic and digital rectal exams. Upon treatment completion at six months, patients then underwent comprehensive evaluations, including tumor biopsy collection and MRI of the rectum, PET and CT scan of the chest, abdomen and pelvis.

A clinical complete response was defined as no evidence of residual tumor on both the digital and endoscopic rectal exams and on the rectal MRI results. Specifically, there must be visual evidence of primary rectal tumor disappearance on a normal digital exam and lack of signal on diffusion-weighted imaging with scar on T2-weighted imaging. Further, each target lymph node must have decreased short axis to less than 0.5 cm diameter.

If patients achieved clinical complete response they entered a nonoperative follow-up window and underwent evaluation every four months. Patients with residual disease would proceed to chemoradiation until clinical complete repsponse was observed. If this was not achieved patients would proceed to surgery. Target enrollment is 30 patients.

The primary objective was overall response rate of PD-1 blockade with or without chemoradiation and pathologic complete response or clinical complete response at 12 months following treatment with Jemperli with or without chemoradiation. Secondary outcomes include safety and tolerability.

Researchers were trying to determine if 25% or more of patients (11 patients) would responde to treatment, a numerical determination made based on the response rate to neoadjuvant chemotherapy of patients with dMMR colon cancer which is approximately 7%.

At the time of the presentation, 18 patients had been accrued to the trial. A majority were women (67%) and had a median age of 54 years (range, 26-78). In terms of tumor staging 22% had T1/2 tumors (disease had spread into the lining of the colon) and 78% had T3 (disease has spread into surrounding tissues) or T4 (disease spread through all layers of the colon) tumors. The mean tumor mutational burden, which determines how many mutations a cancer carries, was 67 mut/Mb (range, 36-106).

A majority (94%) of patients had disease in their lymph nodes and 100% of patients had BRAF V600E wild-type disease, which Cercek noted during a question-and-answer session is because these are patients with left-sided tumors.

“What I’d like to highlight is that the majority of these patients had big bulky tumors (with) 94% node positive,” Cercek said. “The standard of care for these patients would have very likely required all three modalities—chemotherapy, radiation and surgery.”

Cercek presented an overview of the first two patients enrolled and treated with Jemperli. The first patient was a woman aged 38 years who presented with a large, node-positive tumor.

“After completion of six months of Jemperli, we noted disappearance of tumor on endoscopy, and no evidence of tumor on MRI; she achieved a (clinical complete response), which was a very exciting start to the trial.”

The second patient was a woman aged 30 years who presented with approximately three months of rectal bleeding, a change in the caliber of her stool, and pelvic pain for approximately two weeks prior to diagnosis. Cercek noted that she subsequently received a diagnosis with Lynch syndrome. A clear response was noted at six-week follow-up, but Cercek added that a clinical benefit was observed as well.

“After just two doses, she felt significantly better, her bowels had normalized, and she no longer had pelvic pain. At three months, she achieved a clinical complete response (on endoscopy) and on MRI she had a near complete response, so there was still some visible tumor there. On PET (evidence of disease) had also completely disappeared. Her final examination, after completion of six months of therapy was notable for a clinical complete response and I’m very happy to say that this has been sustained now in follow-up for nearly two years.”

In terms of safety no grade 3 or 4 side effects were observed.

“This has the potential to be translated rapidly into areas where access to modern chemotherapy and even more importantly, radiation and surgery may not be available,” Cercek said in her concluding remarks.

In August 2021, Jemperli was approved by the FDA for the treatment of patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options.

“Neoadjuvant (Jemperli) for six months represents a promising new treatment for patients with stage 2/3 dMMR rectal cancer (and) larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival end points are needed,” Ng said. “It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.”

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