Cutsem, Eric Van

Abstract Background Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti–epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. Methods We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. Results Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR–based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. Conclusions Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were >90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.

142 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. FRESCO-2 (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival (OS) with F + best supportive care (BSC) vs placebo (P) + BSC. This subgroup analysis assessed landmark survival of all FRESCO-2 patients (pts), and baseline (BL) characteristics and safety data of pts treated with F who had OS ≥10 months (mos) compared with the intent-to-treat (ITT) population (pop). Methods: Pts were randomized 2:1 to receive F 5 mg or matching P, by mouth, once daily, 3 weeks on, 1 week off, + BSC. Pts had received prior chemotherapy, anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy; and had prior exposure to trifluridine/tipiracil (TAS-102) and/or regorafenib. The hazard ratio (HR) between the two treatment arms was calculated from a stratified Cox proportional hazard model with treatment group as the only covariate in the model. Results: In the ITT pop, OS was improved with F vs P (HR 0.66); OS rates (95% confidence intervals [CIs]) at 6 and 9 mos were 60.4% (55.9–64.9) vs 41.5% (35.0–48.0) and 41.1% (36.4–45.8) vs 28.2% (22.1–34.3), respectively. Progression-free survival (PFS) rates (95% CIs) at 6 and 9 mos were 23.8% (19.7–28.0) vs 1.1% (0–2.6) and 11.3% (8.1–14.6) vs 0.5% (0–1.6), respectively. Of 461 pts who received F, 113 (24.5%) had OS ≥10 mos (range 10.0–18.9) with a median duration of F treatment of 6.3 mos (range 0.7–19.1). Among pts receiving F, a higher proportion (≥10% difference) of pts with OS ≥10 mos had no liver metastases (mets) and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 at BL compared with the ITT pop (Table). In pts with OS ≥10 mos, 61.9% experienced a grade ≥3 treatment-emergent adverse event compared with 62.7% in the ITT pop. Conclusions: Longer-term OS and PFS rates at 6 and 9 mos were higher with F vs P in the FRESCO-2 ITT pop. The data show a higher proportion of pts with OS ≥10 mos had an absence of liver mets and ECOG PS 0 at BL than the ITT pop. The safety profile of F in pts with OS ≥10 mos was consistent with the ITT pop. Clinical trial information: NCT04322539 . BL characteristics of pts treated with F with OS ≥10 mos vs ITT pop. BL characteristic Pts with OS ≥10 mos (n=113) ITT pop(n=461) ECOG PS (0 / 1), % 54.0 / 46.0 42.5 / 57.5 Median time since 1 st CRC diagnosis, mos 52.0 47.2 Primary tumor location at 1 st diagnosis (colon / rectum / both), % 51.3 / 35.4 / 13.3 60.5 / 31.0 / 8.5 Primary site at 1 st diagnosis (colon left / colon right), % 42.5 / 15.9 41.6 / 21.0 Liver mets, % 58.4 73.5 Median duration of mCRC, mos 42.7 37.9 Prior lines of therapy for mCRC (≤3 / >3), % 26.5 / 73.5 27.1 / 72.9 Prior TAS-102, % 46.9 52.1 Prior regorafenib, % 12.4 8.7

4136 Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

687 Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =< 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p < 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p < 0.001), a median PFS of 9.5 vs 7.1 months ( p < 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p < 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

4006 Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]