Cutsem, Eric Van

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts have RAS wild-type and HER2+ mCRC, and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.

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.

4011 Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint. [Table: see text] [Table: see text]

4010 Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age <70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts <70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age<70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts <70 but not those >70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts >70 do not receive the same benefit from combination and/or oral FU as those <70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age [Table: see text] [Table: see text]

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

4099 Background: Colorectal cancer (CRC) incidence and mortality has decreased since the 1970s but the incidence is increasing in young adults (age 20-49). The incidence of early onset CRC (eoCRC) will keep increasing significantly based on the trends of the SEER CRC registry data. There is limited data suggesting eoCRC may have different behaviors compared to traditional CRC (tCRC, age ≥ 50). Methods: Individual pt data of 47184 stage II/III CRC pts from 25 randomized studies in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and treatment-related data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence-free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for stage, performance status (PS), BMI and grade. Results: Using 5% difference between age groups as clinically meaningful cutoff, eoCRC had similar gender, race, ethnicity, PS, risk group, disease sidedness and T stage as tCRC. eoCRC were less likely overweight (30 vs 36%) and more pts had ≥ 12 lymph nodes resected (63 vs 51%). eoCRC had more frequent dMMR status (18 vs 12%), less BRAF mutations (5 vs 13%), and more dMMR/BRAF wild type (WT) status (17 vs 7%). Overall, eoCRC had better OS, DFS, and SAR, with the most significant differences between the < 30 and > = 70 age groups. Similar results were observed within pMMR pts. eoCRC experienced less hematological side effects, diarrhea, and stomatitis, but had more nausea and/or vomiting. Conclusions: eoCRC have unique characteristics; although statistically significant, the clinical differences in outcomes between eoCRC and tCRC are potentially due to the difference seen in extremely young and old pts. eoCRC have a different adverse events panel compared to tCRC. [Table: see text]

4090 Background: EGFR mAbs have become incorporated into clinical practice for the management of mCRC over the last decade. KRAS and NRAS mutations are used as predictive biomarkers and BRAF V600E mutations are associated with an adverse prognosis. The observed TE within biomarker subpopulations has varied between studies. Methods: IPD from randomized trials with head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or BSC) in mCRC, across all lines of therapy (first, second and later), were pooled. Biomarker subpopulations are defined in the table. Overall survival (OS) and progression-free survival (PFS) were compared between groups by Cox model, stratified by studies and adjusted by age, gender, and performance status. TEs were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). Within each biomarker subgroup, EGFR mAb efficacy was explored according to multiple exploratory factors, including line of therapy, type of backbone chemo, gender, sidedness and site of metastasis. Interaction tests were performed. P-values < 0.01 were considered statistically significant to account for multiple comparisons. Results: 5729 pts from 8 studies with data available for ≥ 1 biomarker were analysed. PFS benefits (median 9.2 mos in EGFR mAbs, 8.0 mos in no EGFR mAbs) were confirmed in triple-WT pts, but not for OS (refer to table). No OS/PFS benefits were observed for pts with any of the MT tumors. Exploratory analyses showed a potential detrimental TE of EGFR mAbs in KRAS MT mCRC with liver metastasis (OS: HRadj 1.22, p = .003, pinteraction .0056; PFS: HRadj 1.24, p = .0009, pinteraction .0008). These results were confirmed within the subgroup of pts with all 3 biomarkers available. Conclusions: This is the largest IPD analysis to explore the predictive value of RAS/BRAF biomarkers in mCRC. Our findings demonstrate that there is no evidence of efficacy of EGFR mAbs in KRAS, BRAF and/or NRAS MT mCRC. EGFR mAbs might have a detrimental effect in KRAS MT mCRC with liver metastases. [Table: see text]