100 Percent Response to Preoperative Immunotherapy in Rectal Cancer

Approximately 30-40% of cancers in the rectum, the final part of the large bowel, are locally advanced at diagnosis. It is therefore known that neoadjuvant (preoperative tumor-shrinking) treatment reduces the risk of recurrence and improves survival outcomes. Conventional neoadjuvant treatments for rectal cancer are chemotherapy and radiotherapy. However, approximately 5-10% of locally advanced rectal cancers have a particular genetic alteration called dMMR (mismatch repair deficient= deficient DNA mismatch repair), and tumors carrying this genetic alteration are known to respond well to immunotherapies.   

In a small study of patients with locally advanced dMMR rectal cancer, treatment with the anti-PD-1 agent dostarlimab alone led to a 100% clinical complete response rate. Findings from this study at Memorial Slon Kettering Cancer Center (MSKKM) were reported at the ASCO 2022 Gastrointestinal Cancers meeting and on 5 June 2022 in NEJM.

What Is dMMR?

dMMR (mismatch repair deficient) is an abnormality affecting proper repair of DNA within cells and is identified through genetic tests performed on tumor tissue.

What Is Dostarlimab?

Dostarlimab binds to PD-1, preventing its interaction with PD-L1 and PD-L2, and is a newer-generation immunotherapy in the immune checkpoint inhibitor class.

PD-1 is found on the surface of immune system cells, while PD-L1 and PD-L2 are found on immune cells and some cancer cells.

Blocking the interaction of PD-1 and PD-L1-L2 on cell surfaces helps the body’s immune system fight cancer cells. This immunotherapy was specifically designed to target dMMR endometrial cancer.

The drug Jemperli, whose active ingredient is dostarlimab, had previously received approval

• on 22 April 2021 for patients with recurrent or advanced uterine cancer carrying the dMMR genetic alteration, whose disease progressed during or after prior platinum-containing chemotherapy, and
• on 17 August 2021 from the FDA (US Food and Drug Administration) for adult patients with recurrent or advanced solid-organ cancers carrying dMMR, whose disease had progressed after prior treatments and who had no satisfactory treatment options. 

The presenter of this new study, Dr. Melissa Amy Lumish said: “Among the first 11 patients completing 6 months of treatment with an anit-PD-1 agent alone, we observed an unprecedented 100% complete response. This strategy may uniquely allow patients to avoid chemotherapy and undergo operations with fewer complications… We think this offers a potential new approach to treating dMMR rectal cancer.”

Total neoadjuvant treatment for rectal cancer is a standard approach for all patients diagnosed at stage 2 or 3. Neoadjuvant treatment includes florourasil- and oksaliplatin-based chemotherapy and chemoradiation, followed by rectal cancer surgery (total mesorectal excision). Patients achieving a clinical complete response are now generally offered a nonsurgical treatment option to avoid surgery-related side effects and complications. MSKKM researchers were instrumental in developing a nonsurgical approach to rectal cancer several years ago.

Study Details

Dr. Lumish explained the rationale for immunotherapy in this patient group, reporting that approximately 5% to 10 of all rectal cancers are characterized by dMMr and that metastatic, that is stage 4, dMMR colorectal cancer responds to “immune checkpoint blockade” immunotherapies. Most patients with rectal cancer and dMMR tumors have Lynch Syndrome: young patients of childbearing potential for whom avoiding surgery is desirable. Dr. Lumish said colorectal dMMR tumors are unlikely to respond to fluorourasil alone and that progression during neoadjuvant chemotherapy is high.

A Phase 2 Clinical Study

The single-arm prospective phase II study planned to enroll 30 patients with clinical stage 2 and 3 rectal cancer carrying the dMMR genetic alteration. The cohort currently includes 16 patients, including 11 who have completed dostarlimab treatment. 75% have tumor stage T3 or T4, and 25% have T1 or T2. All but 1 patient have lymph-node-positive disease, and 8 out of 14 have Lynch Syndrome. Dr. Lumish said, “You can see that we did not select patients with low-risk tumors”.

Patients are treated with 500 mg dostarlimab every three weeks for 9 cycles and undergo imaging and endoscopic assessments initially at 6 weeks, and at months 3 and 6. Patients achieving a clinical complete response at the end of treatment have a nonsurgical treatment option, while those with residual disease are reassessed after chemotherapy and radiotherapy, followed by nonsurgical treatment if needed.

The planned primary endpoints of the study were:

• Overall response rate to immunotherapy,
• Clinical complete response 12 months after completion of immunotherapy, and
• Pathological complete response with or without chemoradiotherapy.

100% Clinical Complete Responses

Clinical complete responses were achieved in 11 out of 11 patients (100%) who completed all 6 months of dostarlimab treatment. In other words, all 11 patients achieved both endoscopic and radiographic complete responses. Treatment is ongoing for two patients; one achieved an endoscopic and radiographic clinical complete response before treatment ended.

The figure below shows the endoscopic and radiographic responses over time in patients with locally advanced dMMR rectal cancer treated with dostarlimab. Clinical complete response findings from endoscopic assessments, rectal MRI, and PET-CT are shown for two representative patients at baseline and at months 3 and 6.

Dr. Lumish said none of the 11 patients with a complete response needed chemotherapy or surgery, and they were under surveillance. She also acknowledged that longer-term follow-up is needed to establish the durability of these responses.