Search

PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable, but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Among 121 advanced dMMR mCRC patients treated with CPI at 2 institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on preoperative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggest that residual radiographic tumor may not require systematic resection following response to anti-PD1–based therapy. However, larger prospective studies are warranted.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Despite excellent prognosis for early stage disease, 5-year survival rates in metastatic disease remain low. A small subset of CRC is defined by a deficiency in mismatch repair (dMMR) resulting in high levels of microsatellite instability and are responsive to immunotherapy. Immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1)/programmed death ligand 1 axis and cytotoxic T-lymphocyte antigen 4 have been explored and show robust clinical outcomes with prolonged progression-free survivals in nonrandomized single-arm clinical trials. On the basis of these data, single-agent therapy with pembrolizumab and nivolumab and combination therapy with nivolumab/ipilimumab have been approved by the US Food and Drug Administration for metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ongoing clinical trials are exploring the use of these agents in earlier lines of therapy such as first-line metastatic therapy and adjuvant therapy for stage III CRC. However, resistance to ICIs does occur in a subset of patients and ongoing clinical trials are exploring novel approaches in these PD-1-refractory patients. The aim of this review is to outline the development and decision-making of ICIs in the treatment of dMMR CRC and to discuss ongoing clinical trials in this therapeutic space.

Objective Small bowel adenocarcinoma (SBA) is a rare malignancy with limited evidence regarding outcomes after curative resection of localised disease. We aimed to evaluate presentation and prognostic factors affecting overall survival (OS), relapse-free survival (RFS) and recurrence of SBA. Methods Consecutive patients with completely resected localised SBA (1979–2019) were retrospectively reviewed for presentation, patient and tumour characteristics, perioperative treatment, recurrence, outcomes, and prognostic factors. Results Among 257 total patients, median age was 58 years. Primary location was in the duodenum, jejunum and ileum in 52%, 29%, and 19% of patients, respectively. Median OS was 57.5 months and median follow-up was 40 months. In multivariate analysis, lymph node involvement, lymphovascular invasion, histologic grade and race were independent predictors of RFS, while race, stage and histologic grade were independent predictors of OS. No significant difference in OS or RFS was seen when evaluating the role of perioperative treatment. Median time to diagnosis from first medical evaluation was 31 days and did not change over time. Overall recurrence rate was 56%. Recurrence rate was higher in ileal (77%), than duodenal (54%) and jejunal (65%) SBA (p=0.01). Recurrence presented most commonly as distant metastasis (71%). Proficient mismatch repair was associated with decreased risk of locoregional recurrence (LR) but increased risk of distant recurrence (DR) when compared with deficient mismatch repair (dMMR) in univariate analysis. Conclusions Despite advances in diagnostic modalities, this study did not show any improvement in earlier diagnosis of SBA over the course of the past three decades. The predominant pattern of disease recurrence was distant across all SBA locations, but dMMR status demonstrated a robust predilection for LR as opposed to DR. Perioperative treatment did not improve outcomes; however, a lower stage disease was seen in patients that received neoadjuvant therapy, suggesting further exploration of this approach.

2520 Background: Pembrolizumab (Pembro), anti-PD1 therapy, is FDA approved for refractory microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) advanced/metastatic solid tumors. The robust activity of anti-PD1 therapy in these tumors argues for a neoadjuvant organ-sparing approach. However, the role of anti-PD1 monotherapy in the neoadjuvant setting is unknown. Methods: This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease per RECISTv1.1 and ECOG PS 0/1. Treatment is Pembro 200mg every 3 wks for 8 cycles (6 months) followed by surgical resection with option to continue therapy for 18 cycles (12 months) followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA [highest variant allele frequency (VAF) baseline mutation]. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery. Results: Between 12/2019 and 2/2021, 32 pts were enrolled and treated. Enrolment goal of 35 anticipated to be met by 4/2021. Baseline characteristics included 13 females, median age of 63 yrs (range 26 - 91), Lynch syndrome in 12 pts, BRAF V600E mutation in 11 pts. Tumor type included 24 CRC and 8 non-CRC (1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, 2 pancreatic). At baseline disease was resectable in 23 (72%). Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1). Only one pt progressed after initial SD of -18%. Median follow-up is 6.1 months (range 0.1 - 14). Among the 6 (20%) pts who underwent surgery, pCR was seen in 3 (50%). A non-operative approach (pembro for 12 months) has been chosen in 15 pts and 1-year organ-sparing was seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events (TRAE) were seen in 3 (9%) pts: grade 3 immune hepatitis (2) and grade 3 type 1 diabetes (1). Baseline ctDNA was positive in 17 (53%) pts with a median of 4 mutations per pt (1 - 35) and median highest VAF of 0.9% (range 0.3% to 38.2%). Among 26 pts with successful tumor tissue testing, median tumor mutations were 10.5, range 1 to 21 (Oncomine 134 gene panel). ctDNA decline at 3 weeks was seen in 14/17 (82%) patients. Luminal disease was present in 24 pts with endoscopic response of: CR in 13 (54%), major response 1, pending follow-up evaluation 6, not evaluated 3, and no response in 1. Conclusions: Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation. Clinical trial information: NCT04082572.

152 Background: Monotherapy with immune checkpoint blockade (ICB) is ineffective for patients (pts) with MSS mCRC. Novel approaches to modulate the tumor microenvironment (TME) are needed. Here, we investigate whether the combination of trametinib (T) with durvalumab (D) can alter the immune TME by successfully priming and activating T-cells. Methods: An open-label, single center phase II trial with primary endpoint of immune-related response rate for T+D in refractory MSS mCRC pts (NCT03428126). T is 2mg/day orally starting 1 week prior to D, which is given 1500mg intravenously every 4 weeks. Dose de-escalation strategy performed to identify maximum tolerated dose (MTD). Simon 2-stage design utilized with plans to enroll 29 pts into the first stage, requiring response in 2 or more pts to proceed to stage 2 (n = 15). Results: Demographics for 29 treated pts: 48% female, median age 48 years (range 28-75), and median prior therapies was 2 (range 1-5). No grade (G) 4 treatment-related adverse events (TRAE). The most common G3 TRAE included autoimmune hepatitis (14%) and acneiform rash (10%). G1/2 TRAE included acneiform rash (69%), fatigue (24%) and anemia (21%). No fatal TRAE and 4 pts discontinued treatment due to TRAE. 1 of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an ORR of 3.4%. This pt had an ATM E221fs*14 mutation. 7 pts had stable disease (SD) with median time to progression (TTP) of 5.4 mo (range 3.9-9.3 mo). 1 pt remains on active therapy with SD ( > 10 mo). 5 pts (1 PR, 4 SD) demonstrated decrease in total CEA ng/mL (best percentage reduction: 94%, 95%, 42%, 34% and 21.6% respectively). Median TTP for the entire cohort was 3.2 mo (range 1.1-9.3 mo). Consensus molecular subtypes (CMS) were performed on the primary CRC in 23 pts: 12 CMS2, 2 CMS3, and 9 CMS4. 4 SD pts were CMS2, 1 SD pt was CMS4 and the CMS status of the pt with a PR was unknown. Conclusions: The combination of T+D did not meet efficacy criteria to proceed to the second stage of the study. Analysis of 15 paired on-treatment biopsies is ongoing and will be presented. Utilization of CMS characterization in mCRC clinical trials is feasible and may provide an improved biological understanding of treatment activity. Clinical trial information: NCT03428126.

794 Background: Duodenal adenocarcinoma (DA) is a rare cancer with limited data regarding the pattern of disease recurrence following resection. Methods: A retrospective review of 115 patients with Stage I-III DA from 3/1994 to 6/2018, at a single high-volume cancer center was conducted. Only patients (pts) who underwent a potentially curative surgical resection (R0/R1 margins) and had a postoperative follow-up radiographic evaluation were included. Periampullary adenocarcinomas were excluded. Clinicopathologic features and patterns of recurrence were compared across cohorts. Results: Of 76 patients who met inclusion criteria, 7 (9%) were stage I, 25 (33%) stage II, and 44 (57%) stage III. Histologic grade was moderate in 58% and poor in 38%. Median age was 63 years (range, 29-84), 38% were female, and R0 resection was 97%. Neoadjuvant therapy was given to 14% and adjuvant therapy to 61%. Radiation therapy (XRT) as either adjuvant/neoadjuvant therapy was used in 27%. Median follow-up was 44 (6-293) months. Median time to recurrence was 11mo, with 84% of recurrences occurring within 2 years. Median time to local recurrence (LR) vs. distant recurrence (DR) was 11mo vs. 12mo, respectively, p = 0.42. Stage impacted recurrence rate: 0% in stage 1 vs. 50% stage 2 vs. 71% stage 3 (p = 0.002). Median time to recurrence was 16mo for stage II and 11mo for stage III (p = 0.04). In total, 4 (5%) pts had LR only, 8 (10%) had LR concurrent with DR, and 32 (42%) had DR only. Recurrence distribution was similar across stage II (LR 8%, LR+DR 15%, DR 77%) and stage III (LR 10%, LR+DR 19%, DR 71%). LR was similar in patients that received XRT (10%) compared to those who did not (9%). Most common sites of DR were peritoneal (38%), liver (33%), distant lymph nodes (12%), and lung (10%). Conclusions: The recurrence pattern for resected DA is predominantly distant metastatic disease with the majority of recurrences occurring within the first two years. Future therapies should focus on improved systemic therapy, and surveillance should be most intensive in the first two years.

e15046 Background: Immune checkpoint inhibition (ICKi) for mCRC with deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) demonstrates a high clinical activity rate that appears durable. The impact of immunotherapy on pathological tumor response in dMMR/MSI-H CRC is unknown. Our aim was to assess the pathological response and clinical outcomes following surgical resection in dMMR/MSI-H CRC patients who undergo surgical resection following immunotherapy. Methods: All dMMR/MSI-H mCRC patients treated with anti-PD1/L1 based ICKi between November 2016 and December 2018 at MD Anderson Cancer Center, Houston, Texas and Saint-Antoine Hospital, Paris, France who then underwent surgical resection were included in this retrospective analysis. MSI-H status was determined by ICH in 4 patients and by PCR and ICH in 8 patients. The primary outcome was pathological response in resected surgical specimens following at least 1 cycle of ICKi. Complete pathological response was defined as the absence of residual cancer cells in the surgical specimen. Results: 12 patients (median age at diagnosis 45 years (range 30-70); 10 germline mutations,2 sporadic) of 111 who received ICKi (11%) underwent surgical resection of primary tumor only (n = 5), metastases only (n = 6) or both primary tumor and metastases (n = 1). 42% of patients received PD1 combined with CTLA4 iCKi while 58% received PD1 monotherapy. The median time from ICKi introduction to surgery was 12 months (range 2-28). Prior to surgery 1 patient had complete radiographic response while 11 patients had residual tumor on imaging. 9 surgeries were done with curative intent and 3 with palliative intent. 11 patients achieved pCR while 1 achieved near pCR with rare viable tumor remaining (prior ICKi duration was 2 months). Median follow-up from surgery is 7 months. No patients have progressed following surgical resection. Conclusions: Complete pathological response is achievable with ICKi for dMMR/MSI-H mCRC. For these patients this data supports the curative potential of anti-PD1 based therapy and suggests that residual radiographic tumor may not require surgical resection following response to anti-PD1 based therapy.