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LBA5 Background: Available 2L therapies offer limited clinical benefit in mPDAC with reported mPFS of 3–4 mo and mOS of 6–7 mo. Aberrant RAS pathway activation is the key driver of PDAC, with oncogenic RAS mutations (mut) identified in >90% of cases, most commonly at codon G12. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of the active, GTP-bound state of mutant and wild type RAS. Methods: RASolute 302 (NCT06625320) is a global, randomized, open-label, Ph 3 study in pts with 2L mPDAC and ECOG PS 0-1. Pts were randomized 1:1 to receive daraxonrasib 300 mg PO QD or investigator’s choice of SOC cytotoxic chemo. Dual primary endpoints were OS and PFS by BICR in the RAS G12 mutant (RAS G12) population. Key secondary endpoints included OS and PFS by BICR in the overall population, ORR by BICR in RAS G12 and overall populations. Results: 248 pts were randomized to daraxonrasib and 252 to chemo. Baseline characteristics were balanced between arms. At data cutoff (Feb 10, 2026; mFU: 8.5 mo), all primary and key secondary endpoints were met. Statistically significant, clinically meaningful improvements in OS and PFS were observed with daraxonrasib vs chemo in the RAS G12 and overall populations (Table). Gr ≥3 TRAEs occurred in 43.6% of pts receiving daraxonrasib vs 57.5% receiving chemo. The most common (≥10%) Gr ≥3 TRAEs were rash (13.7%) and stomatitis (12.0%) for daraxonrasib; neutrophil decrease (18.2%) and anemia (16.4%) for chemo. TRSAEs occurred in 10.8% of pts receiving daraxonrasib vs 18.7% receiving chemo. Discontinuation due to TRAEs occurred in 1.2% of pts for daraxonrasib vs 11.2% for chemo. Median/mean daraxonrasib dose intensity was 93.1%/84.7%. Conclusions: Daraxonrasib demonstrated unprecedented improvements in OS and PFS vs chemo in pts with 2L mPDAC with or without an identified tumor RAS mut. Daraxonrasib was generally well tolerated, with a manageable safety profile and with no new safety signals. Results support daraxonrasib as the new SOC for 2L mPDAC. Clinical trial information: NCT06625320 . RAS G12 Overall b Daraxonrasibn=228 Chemo n=231 Daraxonrasib n=248 Chemo n=252 OS Median; mos(95% CI) 13.2(10.0–NE) 6.6(5.4–8.2) 13.2(10.0–NE) 6.7(5.8–8.0) HR(95% CI)P-value 0.40(0.30-0.54)<0.0001 0.40(0.30-0.53)<0.0001 PFS a Median; mos(95% CI) 7.3(6.3–8.1) 3.5(2.9–3.8) 7.2(5.7–7.5) 3.6(2.9–4.2) HR(95% CI)P-value 0.45(0.34-0.59)<0.0001 0.49(0.38-0.64)<0.0001 ORR a %(95% CI) 33.2(27.0–39.9) 11.8(7.8–16.8) 31.6(25.8–38.0) 11.2(7.5–15.9) a By BICR. b RAS G12, G13 or Q61 mut or no RAS mut identified.

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

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.

Abstract Purpose: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI. Experimental Design: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3′ RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Results: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromalHIGH-proliferationLOW”), cluster B (“stromalHIGH-proliferationMED”), and cluster C (“stromalLOW-proliferationHIGH”), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P &lt; 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08–0.45; P &lt; 0.001] and cluster C (HR, 0.25; 95% CI, 0.10–0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non–ICI-based regimens was not significantly different according to cluster. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromalHIGH-proliferationLOW” cluster is associated with a poorer prognosis with ICI treatment.

TPS149 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent could achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI). Tepotinib + the EGFR TKI gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp non-small cell lung cancer and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and therefore provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary antitumor activity, safety and tolerability, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp. A safety run-in (6-12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint:dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis, with RAS/BRAF wild-type, documented previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old and have an Eastern Cooperative Oncology Group performance status of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific METamp heterogenicity. Approximately 42 pts are planned to receive study treatment: ~22 in Cohort A (tepotinib second-line, outside US) and 20 in Cohort B (tepotinib ≥third-line, US only). Primary endpoint:investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR) and PFS (RECIST 1.1), OS, tolerability and safety (NCI-CTCAE v5.0) and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.