CART Cell Cancer Immunotherapy
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All 14 patients who received GlaxoSmithKline’s (GSK’s) immunotherapy Jemperli (dostarlimab) for mismatch repair-deficient (MMRd) locally advanced rectal cancer had a complete response without needing chemotherapy or surgery. Jemperli is an anti-PD-1 monoclonal antibody.

The latest stunning findings from this trial were presented at the 2022 ASCO Annual Meeting. Earlier results, covering just 12 patients, were published in The New England Journal of Medicine this week by researchers at Memorial Sloan Kettering Cancer Center (MSK).

Andrea Cercek, MD, Section Head of Colorectal Cancer and Co-Director of MSK’s Center for Young Onset Colorectal and Gastrointestinal Cancer, and Luis Alberto Diaz, Jr., MD, Head of the Division of Solid Tumor Oncology, led the work.

Besides achieving 100% complete response rate among subjects, the researchers say the study also provides a framework for evaluation of highly active therapies in the neoadjuvant setting—sparing patients chemoradiation and surgery while treating a tumor when it is most likely to respond. They call this new approach “immunoablative” therapy.

“Since MMRd colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesized that locally advanced mismatch repair-deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery, or eliminate the need for additional treatments altogether,” explained Cercek.

In their study, Jemperli was administered every three weeks for six months in patients with MMRd stage 2 and 3 rectal adenocarcinoma, to be followed by standard chemoradiation and surgery. Patients who achieved a clinical complete response were eligible to skip those other treatments.

All 14 patients who initiated treatment so far, and have had at least six months of follow-up, achieved a clinical complete response with no evidence of tumor on MRI, FDG-PET, endoscopic visualization, digital rectal exam, or biopsy. To date, no patients have required chemoradiation or surgery, and no cases of progression or recurrence have been noted during follow-up (up to 25 months). No serious adverse events were observed either.

“Surgery and radiation have permanent effects on fertility, sexual health, bowel, and bladder function. The implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential. As the incidence of rectal cancer is rising in young adults, this approach can have a major impact,” said Cercek.

In August 2021, the US FDA granted accelerated approval to Jemperli for adult patients with MMRd recurrent or advanced solid tumors that progressed on or following prior treatment and when there are no satisfactory alternative treatment options. MMRd status is determined by an FDA-approved test (Ventana MMR Rx Dx).

“While longer follow-up is needed to assess response duration, this is practice-changing for patients with MMRd locally advanced rectal cancer,” said Diaz.

His earlier work helped lead to a paradigm shift in treatment for individuals with MMRd tumors when in 2017 the FDA announced the first pan-tumor approval for adult and pediatric patients with metastatic MMRd tumors that progressed following prior treatment— the agency’s first site-agnostic approval.

“As we advance our research, we envision PD-1 blockade will be evaluated in other MMRd tumors, including not-yet-metastatic pancreatic, gastric, and prostate cancers in the neoadjuvant setting—which could open the door for a pan-tumor approach akin to MMRd in the metastatic disease,” Diaz said.

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