Mazard, Thibault

Background Tumors with mismatch repair deficiency (MMRd) classically display concomitant loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with microsatellite instability-high (MSI-High) status on molecular testing. Nevertheless, a different phenotype can occur in up to 15% of MMRd tumors (unusual phenotype). Data on the efficacy of immunotherapy in this population remain scarce. Methods We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced gastrointestinal MMRd tumors treated with immune checkpoint blockade in the real-world setting. We selected patients with both IHC and MSI assays data available. Unusual MMRd tumors were classified into four distinct groups: (1) isolated loss of PMS2 or MSH6 with MSI-H (isolated/MSI-H), (2) complex loss of MMR proteins with MSI-H (complex/MSI-H), (3) loss of one or more MMR proteins without MSI-H (MMRd-IHC/microsatellite stability (MSS) or MSI-low (MSI-L)), and (4) four MMR proteins retained with MSI-H (retained IHC/MSI-H). Results Out of 759 patients in the IMMUNODIG-MSI cohort, 571 patients met inclusion criteria. Of these, 90 (15.8%) had an unusual phenotype (47 isolated/MSI-H, 19 complex/MSI-H, 16 MMRd-IHC/MSS or MSI-L and 8 retained IHC/MSI-H). Compared with classical phenotypes, patients with a tumor harboring an unusual phenotype had a younger age at treatment (p=0.005), increased RAS mutation (p=0.005), reduced BRAF p.V600E mutation rates (p<0.001), a higher proportion of Lynch syndrome (p<0.001) and a higher prevalence of non-colorectal cancers (p=0.021). After a median follow-up of 28.1 months (mo), there was a significant difference in progression-free survival, with median values of not reached, 66.4 mo, 37.2 mo, 18.3 mo and 5.5 mo for complex/MSI-H, isolated/MSI-H, classical, retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L subgroups, respectively (p<0.001). Notably, objective response rates were 59.1%, 58.7%, and 63.2% for complex/MSI-H, isolated/MSI-H and classical contrasting with 50% and 25% for retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L, with no complete response observed in the latter two. Conclusion Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI-H for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses with MSI-H may represent promising candidates for enhanced immunotherapy efficacy.

3569 Background: Immune checkpoint inhibitors (ICIs) are a standard treatment for gastrointestinal (GI) cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). However, around 50% of patients develop resistance to ICIs, during treatment or after discontinuation. In these patients, the efficacy of reuse an ICI in patients progressing during a previous ICI (rechallenge), or in patients who progressed after discontinuation (reintroduction), remains unknown. The INFLATE study evaluates the efficacy of ICI reuse in patients who progressed on or after discontinuing ICI. Methods: This is a multicenter international retrospective study from the IMMUNODIG cohort, including patients from 34 centers in France, the United States, Italy, Belgium and Spain. All patients received ICI for dMMR/MSI GI cancer. We analyzed patients who had progressed following initial ICI (ICI-1) and subsequently received a rechallenge or a reintroduction with ICI (ICI-2), either monotherapy (mono-ICI) or biotherapy (bi-ICI). Results: A total of 77 patients were included, receiving bi-ICI (N = 34) or mono-ICI (N = 43) during ICI-2. The majority (76%) had a metastatic colorectal cancer. The reason for discontinuing ICI-1 was disease progression in 53% of cases, end of treatment in 15%, toxicity in 5% and other reasons in 26%. Patients who discontinued ICI-1 due to progression received MONO-ICI-2 in 29% of cases and BI-ICI-2 in 71%, whereas those who stopped for other reasons received MONO-ICI-2 in 86% and BI-ICI-2 in 14% of cases. Efficacy results are shown in Table 1. The ORR and DCR were 26% and 79% with MONO-ICI-2, and 16% and 71% with BI-ICI-2. Among patients who discontinued ICI-1 due to progression, BI-ICI-2 (N = 29) achieved an ORR and DCR of 8% and 65%, with a median PFS of 5.5 months (95%CI 4.07-10.4). These outcomes were 17%, 67%, and 3.7 months (95%CI 2.37-NA), respectively, with MONO-ICI-2 (N = 12). For patients who discontinued ICI-1 for reasons other than progression, BI-ICI-2 (N = 5) achieved an ORR and DCR of 60% and 100%, with a median PFS not reached (95%CI 11.5-NR), while MONO-ICI-2 (N = 31) achieved 29%, 82%, and 14.2 months (95%CI 11.2–NR), respectively. Conclusions: This is the first multicenter real-world study evaluating ICI reuse in dMMR/MSI GI cancers. In patients who discontinued ICI for reasons other than progression, reintroduction of ICI therapy upon progression achieves tumor control in 85% of cases. In cases of progression on mono-ICI, Bi-ICI re-challenge achieve tumor control in two-thirds of cases and might be to consider in some patients. ORR % DCR % PFS median (95%CI) OS median (95%CI) Overall N=77 21 76 7.65 months(5.5–11.5) 27.6 months(22.2–55.7) Discontinued ICI-1 due to Progression N=41 11 68 5.03 months(3.7–8.05) 26.7 months(21.1–NR) Discontinued ICI-1 for Other Reasons N=36 33 85 14.22 months(11.24–NR) 27.6 months(22.2–NR)

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

3037 Background: The successes of recent publications on “multi-tumor” circulating markers highlight the relevance of novel universal diagnostic cancer serum biomarkers. Since the Wnt/ß-catenin/Tcf4 pathway, activated in many tumors, induces the GAST Gene encoding progastrin synthesis, we hypothesized that progastrin, easily measurable in the blood, might be a “multi-tumor” diagnostic biomarker. Methods: Progastrin levels were measured in the blood samples of 1319 patients with 12 different cancer origins, and compared to those of 557 asymptomatic 18-75 years old blood donors. Moreover the longitudinal kinetics of progastrin concentrations were serially assessed during treatments in 168 patients with ovarian cancers enrolled in the randomized CHIVA trial (NCT01583322, GINECO), 191 patients with peritoneal involvement from gastro-intestinal cancers enrolled in BIG-RENAPE trial (NCT03787056), and in 95 HCC patients. The progastrin was measured using an ELISA test developed by ECS Progastrin (Prilly, Switzerland). Results: Compared to healthy blood donors, progastrin was found at higher concentrations in the plasma of cancer patients: median 4.47 vs 0.20 pM, P < 0.0001; diagnostic discriminative power, ROC analysis AUC = 0.86 (95% CI, 0.83-0.89; P < 0.0001). Progastrin levels were found elevated in all cancer groups, regardless of disease stages, and of pathology origins: ROC AUCs ranged from 0.71 to 0.93, all P < 0.0001 (Table). The longitudinal progastrin changes during treatments, suggest relationships to tumor burden, and potential monitoring value. Conclusions: Progastrin is a novel ubiquitous cancer biomarker, easily detectable in the blood using an affordable ELISA test (CancerRead Lab test(R)). It may change the future paradigms about screening (in particular for populations at higher or lower risks of cancer), cancer diagnostic & monitoring. [Table: see text]