Gramont, Aimery de

107 Background: The "No Placebo Initiative" demonstrated that the survivals of patients (pts) receiving placebo in a salvage-line setting, exhibited no significant difference across trials (CORRECT, RECOURSE, CONCUR and TERRA). Therefore, we believe that a nomogram can be generated using the ARCAD database to predict survival of pts who completed standard therapy. Methods: Of 40,889 Individual patient data (IPD) from 59 studies, 723 pts received placebo from 4 randomized studies were pooled. The potential prognostic factors considered include BMI and Age. Imputed datasets were constructed by a multiple imputation method since the original dataset contains some missing values. Overall survival (OS) was defined as the time from randomization to death from any cause. Multivariate Cox proportional hazards models for OS were estimated based on the variables showing clinically and statistically significant by univariate analysis. Prediction performance of the final model was evaluated using the concordance index for survival data and calibration plots. Results: From univariate and multivariate analysis, ECOG performance status, Royal Marsden Hospital score (calculated by albumin level, LDH level, and number of metastatic site), primary site location, liver meta, peritoneal meta were selected as variables. We successfully developed a highly accurate nomogram to predict post-standard treatment prognosis for pts with mCRC. Concordance index for OS was 0.66. Conclusions: Although further validation in other cohorts is needed, this nomogram could be very useful to estimate the survival for clinical practice and enrolling in clinical trials. [Table: see text]

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.

3588 Background: Although anti-EGFR antibody plus doublet chemotherapy has become the standard of first-line treatment for RAS wild-type (wt), left sided metastatic colorectal cancer (mCRC), the optimal molecular-targeted therapy for RAS wt, right-sided mCRC is not clear. Methods: To evaluate the efficacy between anti-EGFR antibody vs. bevacizumab combination therapy, from 40,889 Individual patient (pt) data from 59 studies in ARCAD mCRC database, 723 pts with RAS wt, right-sided mCRC who received a first-line molecular-targeted therapy with backbone chemotherapy (FOLFOX/FOLFIRI when anti-EGFR antibody combination, and FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI when bevacizumab combination) were selected from 10 randomized studies (FIRE-3, CALGB80495, CRYSTAL, PRIME, CAIRO2, OPUS, TRIBE, TRIBE2, ATOM, and CCOG1201). Primary objective was overall survival (OS), and secondary objectives were progression-free survival (PFS) and overall response rate (ORR); Hazard ratio (HR) and Odds ratio (OR) were adjusted for ECOG-PS, age, and gender. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) as sensitivity analysis were also performed. Secondary analyses were limited to BRAF wt pts. Results: Anti-EGFR antibody and bevacizumab were administrated in 329 and 394 pts, respectively, of whom 162 and 151 pts were BRAF wt, respectively. Baseline characteristics were as follows (anti-EGFR antibody/bevacizumab): median age, 63.0 years both; female, 47.1/46.4%; and ECOG-PS 0, 53.2/65.2%. The OS and PFS were significantly prolonged in pts receiving bevacizumab combination therapy compared to those receiving anti-EGFR antibody combination therapy (Table). These trends were more pronounced when limited to BRAF wt pts (Table). There were no significant differences in ORR for both overall and BRAF wt pts. These results were similar in the sensitivity analysis (Table). Conclusions: For patients with RAS wt or RAS/ BRAF wt, right-sided mCRC, bevacizumab combination therapy is preferred first-line treatment. [Table: see text]

3566 Background: According to the various types of clinical trials for metastatic colorectal cancer (mCRC), ETS and DpR are suggested as the surrogates of OS. Whereas associations between ETS/DpR and OS/PPS in the era of chemotherapy (chemo) +anti-EGFR antibody (ab)/bevacizumab (bev) in 1st line therapy have not been elucidated. Methods: From 40,889 Individual patient data (IPD) from 59 studies in ARCAD mCRC database, 2,138 treatment-naïve pts with RAS wild-type (wt) mCRC were selected from 7 randomized studies (PRIME, CAIRO2, CRYSTAL, OPUS, CALGB80495, WJOG4407G, ATOM) of chemo with/without anti-EGFR ab or bev. The ETS was defined as 20%≥ tumor shrinkage at 8 ± 2wks (ETS+: ≥20%, ETS-: <20%). Multivariate Cox regression models for OS/PPS were performed to investigate associations between ETS+ and ETS- by primary tumor location (overall/left-sided/right-sided), adjusting for potential confounders. DpR was defined as tumor shrinkage at nadir. OS/PPS were evaluated across quartile limits of DpR by multivariate Cox regression models. Results: In pts with overall or left-sided RAS wt mCRC, adjusted hazard ratios (HRs) of OS/PPS between ETS- and ETS+ for chemo +anti-EGFR ab, chemo +bev, and chemo alone showed great improvement, respectively (Table). In pts with overall or left-sided RAS wt mCRC, HRs of ETS for OS/PPS are higher in pts treated with chemo +anti-EGFR ab compared to those treated with chemo +bev or chemo alone. Compared to the pts with highest quartile (defined as ≥ 75th percentile (Q3)) of DpR, HRs of OS/PPS for lower quartile groups showed upward trends in pts with RAS wt & overall (Table). Conclusions: ETS/DpR in pts with RAS wt mCRC might be a potential prognostic marker of OS/PPS regardless of targeted therapy and primary tumor location. Superior prognostic values of ETS+ are expected in pts treated with anti-EGFR ab. [Table: see text]

3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P < .001) and less SS (31 vs 47%; P < .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P < 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT<.001). Conclusions: In pts with multiple sites mCRC, a statistically sig OS bnf of BEV added to CT was observed mainly among pts without lung mets. The overall effect of CT partner choice when combined with BEV can be different. In pts with single site, BEV did not seem to improve OS but the evaluation of efficacy of BEV in presence or absence lung mets was based on small number of pts and needs to be evaluated in trials with larger pts sample, especially trials including pts with single site lung mets. [Table: see text]

PURPOSE Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

3606 Background: Standard adjuvant CT for stage III CC are FOLFOX and CAPOX. Recently, IDEA study separated stage III patients (pts) into low risk (T1 to 3, N1) and high risk (T4 or N2). We recently confirmed benefit of OX in both risk groups. However, we observed a difference in the two high-risk subgroups, with benefit in N2 but not in T4 (Margalit O et al; Clin Colorectal Cancer 2021). This prompted us to compare outcomes (OS/TTR) between treatment with OX vs. without OX within sub-stage III CC groups defined by T and N. Methods: We pooled 4941 stage III CC pts from the three studies evaluating 6 months of CT with fluoropyrimidine (FP) ± OX: MOSAIC, C-07 and XELOXA. Baseline characteristics were compared using χ2 and t-test. OS was compared between OX and no OX in T and N subgroups. Kaplan-Meier analyses, adjusted and unadjusted Cox models stratified by study were used. Sub-groups classification was done according to OX benefit and verified by interaction test (Int) considered as significant with a P<0.1. We considered for recommendation of using OX-based adjuvant CT, 1) significant benefit in OS, 2) significant Int between substage and adjuvant therapy, and 3) the three individual trials showing similar results (benefit or non-benefit of OX). Results: In stage III population, T3 pts were 74.9%, T1-2 12.4%, T4 13.1%, while N stage was N1 64.7% and N2 35.3%. Population was well balanced according to treatment allocation in most subgroups. A significant benefit of OX was only observed in T3N1 and T3N2 (OS HR 0.76). Whatever N stage, there was no significant benefit of OX in the T1-2 and T4 subgroups. The effect of OX+FP vs FP alone in OS of the three studies differed between T3 and T1-2 subgroups (P = 0.047). Interaction was borderline between T3 and T4 subgroups (P = 0.10) but there was no interaction between T1-2 and T4 subgroups (P = 0.429). A benefit of OX in TTR remained in the T4 population. Discrepancy between advantage in time to relapse (TTR) and no advantage in OS was not explained by survival post relapse. Conclusions: Our analysis suggested that pts with T1-2N1-2 and T4N1-2 disease had no OS benefit of addition of OX to FP. The good survival achieved with FP alone in T1-2N1-2 pts (5-yr OS 89%) question the addition of OX. In the T4 population our results suggested that benefit of OX was limited and that further studies should assess this issue or at least stratify pts on T stage in the future adjuvant trials in CC. [Table: see text]

3578 Background: Monoclonal antibodies (mab) targeting EGFR are recommended in L1 treatment (trt) for mCRC in patients (pts) with RAS wild-type (WT) tumor and primary left CRC. ARCAD database contains individual data of randomized trials that evaluated anti-EGFR mab plus chemotherapy (CT). In this analysis we aimed to evaluate anti-EGFR benefit in mCRC with lung mets, either as single site or multiple sites. Methods: Individual pts data from four trials (PRIME, CRYSTAL, COIN, OPUS) comparing CT +/- anti-EGFR were pooled. KRAS status was not required at inclusion to these studies. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method, prognostic value of lung mets was evaluated by stratified Cox models in pts groups defined by KRAS status. The predictive value was evaluated by interaction test (Int) between trt and lung mets status in pts group defined by KRAS status and considered as significant with a P < 0.1. Results: 3681 pts with known KRAS status were included, 2171 WT and 1510 mutant (MT). Pts characteristics were well balanced. Significant median OS benefit of anti-EGFR was observed in the whole KRAS WT population and in the left colon and rectum subgroup but not in the right colon subgroup. In pts with KRAS WT single site mets, a non-significant benefit of anti-EGFR was observed only among pts without lung mets (N = 642). In pts with lung single site mets (N = 129), a significant benefit ( P= 0.018) in the KRAS MT population (N = 55) was observed, but Int was non-significant ( P =0.157). In pts with KRAS WT and multiple without lung mets sites (N = 673), no benefit of anti-EGFR was observed and Int was significant ( P= 0.054). Pts with KRAS MT multiple sites with (N = 656) or without (N = 397) lung mets, had no benefit of anti-EGFR. The same findings were found in the left primary pts and in the two fluoropyrimidine backbone. PFS analyses confirm the OS results. Conclusions: In this ARCAD analysis pts with lung mets as a single site appear to benefit from anti-EGFR L1 therapy in case of KRAS MT. This unexpected result based on a limited sample size cannot be explained on the knowledge of anti-EGFR therapy. Furthermore, pts with multiple mets sites have a benefit of anti-EGFR therapy only in the presence of lung mets even in KRAS WT left primary tumor. These findings need further confirmation and may initiate the search for a specific molecular phenotype associated with lung mets in CRC pts. [Table: see text]

3572 Background: Early onset colorectal cancer (eoCRC: disease diagnosed < 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HRadj], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p<0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]