Excitement at rectal cancer immunotherapy breakthrough

A ground breaking ‘immunoablative’ neoadjuvant immunotherapy clinical trial at Memorial Sloan Kettering Cancer Center (MSK) has reported a 100% complete response rate in MMRd locally advanced rectal cancer.

Breakthrough findings were presented at the2022 ASCO Annual Meeting and published in The New England Journal of Medicine by researchers at Memorial Sloan Kettering Cancer Center (MSK)confirming a clinical complete response in all 14 patients who received the immunotherapy treatment dostarlimab as a first-line treatment for mismatch repair-deficient (MMRd) locally advanced rectal cancer. This new approach of ‘immunoablative’ therapy uses immunotherapy to replace surgery, chemotherapy and radiation to remove cancer.

MSK’s Andrea Cercek, MD, Section Head of Colorectal Cancer and Co-Director of the Center for Young Onset Colorectal and Gastrointestinal Cancer, and Luis Alberto Diaz, Jr, MD, Head of the Division of Solid Tumor Oncology, led this ground breaking clinical trial — which saw a 100%complete response rate among its patients. The study also provides a framework for evaluation of highly active therapies in the neoadjuvant setting, where patients are spared from chemo radiation and surgery while treating the tumour when it is most likely to respond.

Study details and findings

“Since MMRd colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesised that locally advanced mismatch repair-deficient rectal cancer is sensitive to checkpoint blockade and Excitement at rectal cancer immunotherapy breakthrough may alter the requirements for chemo radiotherapy and surgery, or eliminate the need for additional treatments altogether,” explains Dr Cercek.

Left to right) Sascha Roth, Dr. Luis Diaz, Imtiaz Hussain, Dr. Andrea Cercek, Avery Holmes and Nisha Varughese. Image courtesy of
MEMORIAL SLOAN KETTERING.

MSK researchers conducted a prospective study in which single agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every three weeks for six months in patients with mismatch repair-deficient stage 2 and 3 rectal adenocarcinoma, to be followed by standard chemo radiation and surgery. Patients who achieved a clinical complete response were eligible for omission of chemoradiation and surgery.

All 14 who initiated treatment on the trial and have had at least six months of follow-up achieved a clinical complete response with no evidence of tumour on MRI, FDG-PET, endoscopic visualisation, digital rectal exam, or biopsy, which satisfied the study’s co-primary endpoint. To date, no patients have required hemoradiation 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. As researchers found the elimination of tumours following six months of therapy with PD-1 blockade, it enabled them to omit both chemoradiation and surgery and to proceed with observation alone.

Treatment implications

“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,” says Dr. Cercek. “While longer follow-up is needed to assess response duration, this is practice-changing for patients with MMRd locally advanced rectal cancer,” says Dr. Diaz. His early work led to a paradigm shift in treatment for individuals with MMRd tumours in 2017 when the FDA announced the first pan-tumour approval for adult and paediatric patients with metastatic MMRd tumours that progressed following prior treatment. This was the FDA’s first site-agnostic approval. “As we advance our research, we envision PD-1 blockade will be evaluated in other MMRd tumours, including not-yet-metastatic pancreatic, gastric, and prostate cancers in the neoadjuvant setting — which could open the door for a pan-tumour approach akin to MMRd in the metastatic disease.”

Volume 23 – Issue 3, Summer 2022

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