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Can immune checkpoint inhibitors plus surgery cure advanced mismatch repair-deficient cancer?
Background
There is a strong body of evidence supporting use of immune checkpoint inhibitors (ICI) in unresectable mismatch repair-deficient (MMRd) / microsatellite unstable (MSI) high colorectal cancer (mCRC); anti-PD-1 therapy is the standard of care for first-line treatment of mCRC (Andre, NEJM 2021). Emerging evidence also demonstrates high rates of complete pathological response (pCR) following neoadjuvant ICI in patients with stage I-III MSI colon cancer (Chalabi, Nature 2020) and in MSI gastric cancer (Andre, ASCO GI 2022). This leads to the question of whether ICI with or without surgery could lead to cures in advanced MSI cancers. Herein we describe our single institutional experience of immunotherapy followed by surgery in MSI intestinal cancers.
Methods
In this retrospective series the institutional electronic health record was reviewed for patients with ICI treated MSI intestinal cancers with subsequent surgical resection. Demographics and clinicopathological characteristics were collected, with ICI therapy details and toxicity, radiological response and operative details. Post-operative histology was reviewed. Overall survival was calculated using the Kaplan-Meier method.
Results
Five patients were identified; 5 (100%) female. Mean/median age was 37/46 years (range 22-78). Four (80%) had MLH1/PMS2 deficient cancers, 1 was MSH2/MSH6 deficient. One had germline MLH1 mutation, one germline pending. Two (40%) had concurrent tumour BRAF V600E mutation, two (40%) had KRAS G12D mutation. Four (80%) had colon cancer (1 ascending colon, 1 synchronous ascending colon and hepatic flexure, 1 transverse colon, 1 rectosigmoid); 1 patient jejunal adenocarcinoma. Three colon cancer patients had lymph node metastases distant from the primary, one had local pelvic side wall recurrence, one had direct invasion of liver and pancreas. All patients received ICI with initial palliative intent (1 ascending colon 2nd line nivolumab, 1 synchronous tumours 1st line nivolumab/ipilimumab, 1 rectosigmoid 2nd line nivolumab/ipilimumab, 1 transverse 1st line pembrolizumab, jejunal 1st line nivolumab). Two patients had admissions with ICI related fevers, 1 experienced ICI G3 pneumonitis and 1 experienced G3 hepatitis. All patients had radiological response to ICI. Two patients (transverse colon / jejunal cancer) experienced stricture in responding primary tumour and required surgery. One ascending colon cancer had surgery a symptomatic PET-avid mass, 1 synchronous cancer patient had right total mesocolic excision, partial hepatectomy and Whipples. One recurrent rectosigmoid colon cancer had total pelvic exenteration following ICI and radiotherapy. All patients had R0 resection. Two patients had pCR (ypT0N0) (ascending colon, rectosigmoid colon); both complete responders had experienced ICI related toxicity. Other patients’ stage were transverse colon (ypT3N0), jejunal cancer (ypT0N1) and synchronous tumours (ypT4N0 and ypT2N0). After median follow up of 15 months, no patient has recurrent disease. Median overall survival is not reached.
Conclusions
In this series we demonstrate that a combination of ICI and surgery can render patients with advanced MSI cancers disease free by downstaging previously unresectable cancers and eliminating distant metastases. As complete responses were demonstrated in two patients with suspicious pre-operative radiological findings on resection, improved imaging techniques or ctDNA may be helpful in guiding which patients require surgery in future.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
