mCRC Pts Research Articles

Long-term survival outcomes following resection of lung metastases (LM) from a colorectal primary.

50 Background: Liver metastatectomy in oligometastatic colorectal cancer (CRC) can result in long-term disease control1. The benefit of resecting LM is unclear, with good survival outcomes from medical therapy (MT) alone and a recent randomised controlled trial failed to demonstrate an overall survival (OS) benefit2. Methods: We examined TRACC (Treatment of Recurrent and Advanced Colorectal Cancer), a multisite registry for metastatic colorectal cancer (mCRC) patients (pts) from September 2002 – July 2021, focusing on the longer-term outcomes for pts with lung only metastatic disease (LOM). Key clinicopathological, treatment and outcome variables were analysed. Survival outcomes were determined by Kaplan-Meier method. Results: Of 3928 pts, 341 (8.7%) had LOM. The median OS was significantly improved for LOM vs. all mCRC pts (44.5 months vs. 24.8 months, p = <0.0001). Of 341 LOM pts, 142 (42%) had lung resection (LRes),128 (38%) had MT, 71 (20%) best supportive care. Key clinicopathological characteristics are summarised in Table. OS was significantly longer for LRes vs. MT (3yrs-80.1% vs. 41.9%, p = <0.0001, 5 yrs-65.2% vs. 21.1%, p = 0.0001). 10 yr survival for LRes was 50%, with no survivors from MT. The median palliative chemotherapy free interval was 13 months (95% CI 3.1 – 18.7) with recurrence after LRes/death. 20/142 (14%) of the LRes pts had recurrent LRes (median time to repeat resection of 11.4 months, median survival of 66.9 months from repeat LRes). Conclusions: LM from mCRC have an indolent course, with good survival outcomes with MT alone. LRes provides a clinically meaningful palliative chemotherapy free interval and long term survival in selected pts. Significant differences in prognostic factors may have contributed to the observed survival differences between LRes and MT. Reference Dexiang Z, Li R, Ye W, Haifu W, Yunshi Z, Qinghai y, Shenyong Z, Bo X, Li L, Xiangou P, Haohao L, Lehi Y, Tianshu L, Jia f, Xinyu Q, Jianmin X. Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. Ann Surg Oncol. 2012 Sep;19(9):2860-8. doi:10.1245/s10434-012-2356-9.Epub 2012 Apr 12. PMID: 22526903. Treasure, T., Farewell, V., Macbeth, F. et al. Pulmonary Metastatectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials 20,718 (2019). https://doi.org/10.1186/s13063-019-3837-y [Table: see text]

Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer.

Simple SummarySeveral studies suggested an enhanced efficacy of conventional treatments (CT, i.e., chemotherapy +/− targeted therapy) administered after immune checkpoint inhibitors (ICI) in certain tumor types, but no data are available concerning metastatic colorectal cancer (mCRC) patients harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). The aim of our study was to assess the outcomes of dMMR/MSI mCRC patients receiving CT after ICI failure. We retrospectively collected clinical data from a multicentric cohort of 31 patients. Although limited by the small number of patients, our results did not suggest improved outcomes with CT in our population, and no significant association with previous ICI efficacy or with anti-VEGF agents was evidenced. However, prolonged disease control was observed in several cases, suggesting that some patients might derive an unexpected benefit from post-ICI treatments. With ICI becoming the standard of care in patients newly diagnosed with dMMR/MSI mCRC, these results might help to inform clinical decision-making and to guide future therapeutic strategies for these patients.Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

386O Exploratory biomarker analysis of DESTINY-CRC01, a phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd, DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC)

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. In primary analyses of DESTINY-CRC01 (NCT03384940), T-DXd showed antitumor activity and a manageable safety profile in HER2+ mCRC pts (Siena ASCO 2020). We present exploratory biomarker data and its relation to response in HER2+ mCRC. Pts with centrally confirmed HER2-expressing, RAS wildtype mCRC that progressed after ≥2 prior regimens received 6.4 mg/kg of T-DXd Q3W in 3 cohorts (A: HER2+, IHC3+, or IHC2+/ISH+, n = 53; B: IHC2+/ISH−, n = 15; C: IHC1+, n = 18). Circulating tumor DNA (ctDNA) samples at baseline (BL), cycle 4, day 1, and end of treatment, along with BL serum HER2 extracellular domain (HER2ECD) were analyzed as exploratory biomarkers. To correct for variation in plasma tumor fraction between samples, adjusted plasma ERBB2 copy number (ApCN) was calculated based on the maximum variant allele fraction (Siravegna CCR 2019). Exploratory cutoff values for ApCN in ctDNA and HER2ECD were defined as those with the maximum value of the Youden index for ORR. In cohort A, higher clinical response to T-DXd was observed with higher tumor or plasma HER2 expression (Table). Antitumor activity of T-DXd was seen in pts with or without ctDNA-detected activating RAS or PIK3CA mutations and was lower in pts with blood TMB high vs low (Table). In paired ctDNA samples collected at BL and disease progression from 30 pts, acquired alterations were observed in several genes, but none was common across pts (n = 12).Table: 386OORR by BL Biomarker GroupBiomarker GroupN = 53ORR, % (95% CI)Tumor HER2 ExpressionHER2+5345.3 (31.6-59.6)IHC3+4057.5 (40.9-73.0)IHC2+/ISH+137.7 (0.2-36.0)Blood biomarkersERBB2 ApCN≥30.92462.5 (40.6-81.2)<30.9 or not detected2832.1 (15.9-52.4)ERBB2 plasma amplificationFocal3655.6 (38.1-72.1)Aneuploidy or not detected1625.0 (7.3-52.4)HER2ECD≥23.5 ng/mL2263.6 (40.7-82.8)<23.5 ng/mL2729.6 (13.8-50.2)NRAS/KRAS mutationActivating633.3a (4.3-77.7)WT or other4647.8 (32.9-63.1)PIK3CA mutationActivating633.3 (4.3-77.7)WT or other4647.8 (32.9-63.1)TMBHigh (≥20 mut/Mb)1323.1 (5.0-53.8)Low (<20 mut/Mb)3953.8 (37.2-69.9)aResponders had KRAS mutations. Open table in a new tab aResponders had KRAS mutations. This exploratory analysis of biomarker data in HER2+ mCRC pts administered T-DXd indicates that antitumor activity appears to be correlated with BL HER2 expression or amplification in tumor and liquid biopsy. Further investigations into potential mechanisms of resistance to and patient selection for T-DXd in HER2+ mCRC are warranted.

455P Concordance of baseline RAS mutational status (ms) between tissue and cell-free DNA (cfDNA) and association with overall response rate (ORR) in first-line (1L) metastatic colorectal cancer (mCRC) patients (pts): PERSEIDA study (cohort 2) (NCT02792478)

Tumor-tissue biopsy is the standard of care (SOC) to assess RAS & BRAF ms in mCRC pts. However, the analysis of circulating cfDNA has the advantage of evidencing genetic tumor heterogeneity. We explored the occurrence of KRAS, NRAS and BRAF sequence variants (sv) using cfDNA in 1L SOC RAS wt mCRC pts. The concordance of RAS ms between tissue and cfDNA, and the association of cfDNA RAS ms and ORR were also explored.

508TiP PRODIGE 68 - UCGI 38 - SOREGATT: A randomized phase II study comparing the sequences of regorafenib (reg) and trifluridine/tipiracil (t/t) after failure of standard therapies in patients (pts) with metastatic colorectal cancer (mCRC)

First-line treatment for mCRC pts consists of a fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin and/or irinotecan) with VEGF or EGFR inhibitors. Once these treatment options have been used, or are no longer appropriate, pts are eligible for either reg or t/t treatment. Although both treatments are approved in mCRC, no randomised trial has investigated the sequence of reg and t/t. The optimal strategy to extend survival while maintaining quality of life still needs to be determined.

LBA20 FOLFOXIRI plus bevacizumab (bev) plus atezolizumab (atezo) versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer (mCRC) patients: Results of the phase II randomized AtezoTRIBE study by GONO

FOLFOXIRI/bev is an upfront therapeutic option for selected mCRC pts. Immune checkpoint inhibitors (ICIs) reported remarkable achievements in dMMR but not in pMMR mCRC. The association of cytotoxics and bev may promote the sensitivity to ICIs increasing the exposure of neoantigens, inducing immunogenic cell death, and increasing the immune infiltration in tumor microenvironment while reducing the activity of Tregs.

492P Vitamin D deficiency in metastatic colorectal cancer (mCRC) worsens survival and correlates with significant peripheral inflammatory/immune cell changes

Vitamin D (Vit.D) deficiency is a poor prognostic factor in mCRC patients (pts). To evaluate if this is attributable to an impaired immunity boosting effect, we analysed peripheral inflammatory/immune components in Vit. D deficient mCRC pts.

478P TA-ness classification discriminates RAS wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts) who may benefit from antiEGFR treatment

RAS/BRAF wt mCRC pts could potentially benefit from antiEGFR treatment but only 50% of them respond. Data from CRCAssigner (CRCA) and Consensus Molecular Subtypes (CMS) classification identified transit-amplifying (TA)/CMS2 as more sensitive to antiEGFR. We aimed to evaluate different gene-expression–based classifiers for identification of RAS wt pts that may benefit from antiEGFR.

493P Impact of age on the activity of aflibercept plus FOLFIRI in metastatic colorectal cancer (mCRC): Real world data from the QoLiTrap study

Median ages at CRC diagnosis and death are 67 and 72 years, respectively. Older patients (pts) are underrepresented in clinical trials and often undertreated in daily practice. Here, we report the impact of age on effectiveness, quality of life (QoL) and safety of aflibercept plus FOLFIRI in mCRC pts previously treated with an oxaliplatin-containing regimen.

P-73 The role of site of metastatic resection in metastatic colorectal cancer patients: A mono-institutional cohort study

Approximately 50%-60% of colorectal cancer (CRC) patients (pts) develop metastases, usually to liver and lung. When feasible, metastatic resection (MR) is the only potentially curative option in the multimodal management of mCRC pts. Few studies have compared survival outcomes based on different surgical sites with contrasting data. Hence, we retrospectively analyzed mCRC pts who underwent radical lung and/or liver resection at our institution, investigating the impact of resection site on overall survival (OS).

Abstract 2618: Staged analysis of standard of care tumor molecular testing among patients with metastatic colorectal cancer in the community health system setting

Abstract Background: National Comprehensive Cancer Network guidelines have recommended metastatic colorectal cancer patients (mCRC pts) undergo BRAF, KRAS, NRAS, and microsatellite instability/mismatch repair deficiency (MSI/MMR) testing since 2015. Previous studies have reported molecular testing rates from academic and community cancer centers, but there is a lack of information on testing rates in community health systems (HS) which account for approximately half of US cancer care. Methods: Tumor molecular testing rates were assessed in a first stage analysis for pts with mCRC in HS, in order to inform a second stage analysis focused on treatment decisions and pt outcomes. For the first stage analysis, we randomly selected 200 pts (50 pts from each of 4 HS sites) diagnosed with mCRC between 1/1/2015 and 9/1/2020. The 200 pts were identified through technology-enabled curation, followed by retrospective review performed by certified tumor registrars. An anticipated cohort of 1000 evaluable pts is planned for the second stage analysis. Results: 53% of pts were tested for all four biomarkers at some point during their care (Table). Pts more likely to have been tested include those: from HS Site 1 (P = 4.2x10-5); age &amp;lt;65 years old at mCRC diagnosis (P = 0.014); and with commercial insurance (P = 0.015). Among pts tested, the median times from metastatic diagnosis to BRAF, KRAS, and NRAS testing results were 35, 33, and 34 days, respectively. Conclusion: This first stage analysis of molecular testing in mCRC pts revealed variation in testing rates by site, biomarker, and patient characteristics, which may in part be explained by the implementation of a precision medicine testing program at HS Site 1. A second stage analysis assessing the impact of biomarker testing on treatment decisions and pt outcomes will be guided by this initial characterization of testing rates and possible confounders. Biomarker testing rates among metastatic colorectal patients across four health system sitesSite 1 (n=50)Site 2 (n=50)Site 3 (n=50)Site 4 (n=50)BRAF tested43 (86%)25 (50%)24 (48%)26 (52%)Count (%)KRAS tested44 (88%)35 (70%)32 (64%)35 (70%)Count (%)NRAS tested42 (84%)23 (46%)26 (52%)30 (60%)Count (%)MSI/MMR tested49 (98%)37 (74%)44 (88%)44 (88%)Count (%)All biomarkers tested40 (80%)19 (38%)20 (40%)26 (52%)Count (%) Citation Format: Chenan Zhang, Mahder Teka, Francesca F. Coutinho, Joseph R. Burkhart, Louise E. Widmer, Ronda G. Broome, Mary T. Tran, Michael A. Thompson, Antony M. Ruggeri, Jennifer J. Godden, James L. Weese, Douglas J. Reding, Anna B. Berry, Yanina Natanzon, Thomas D. Brown. Staged analysis of standard of care tumor molecular testing among patients with metastatic colorectal cancer in the community health system setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2618.

Abstract CT129: ARC-3: Updated results of etrumadenant (AB928) + modified FOLFOX-6 (mFOLFOX-6) in metastatic colorectal cancer (mCRC) patients

Abstract Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases immunosuppressive extracellular adenosine, which can bind and activate the A2a and A2b receptors on immune cells, diminishing the effectiveness of the anti-tumor immune response. Concomitant dual adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. Etrumadenant (etruma, AB928) is the first clinical-stage small-molecule, selective dual antagonist of A2aR and A2bR for which combination data with mFOLFOX-6 in mCRC were previously presented1,2. Here we present updated results for safety in all patients (pts) and efficacy in 3L+ pts. Methods: ARC-3 (NCT03720678) was a phase 1/1b, multicenter, open-label study to evaluate etruma + mFOLFOX-6 in pts with mCRC. Eligible pts had histologically confirmed mCRC with ≥1 measurable lesion. Pts received 75 mg (phase 1 only) or 150 mg etruma orally once daily (QD) + mFOLFOX-6. The primary objective was to assess the safety of the combination; secondary objectives included evaluation of clinical activity. Results: As of 20Nov2020, 44 pts were enrolled and received etruma (75mg: n=4; 150mg: n=40) + mFOLFOX-6. Etruma-related AEs were reported in 34 pts and were mostly Grade 1 or 2; those reported in &amp;gt;30% of pts were fatigue and nausea. One pt had an etruma-related Grade 3 acute kidney injury and there were no Grade 4-5 etruma-related SAEs. There were 22 efficacy-evaluable 3L+ subjects, all of which had received prior FOLFOX and/or FOLFIRI. In this subgroup, the ORR was 9.1% and the median PFS and OS were 3.9 and 15.7 mos respectively. Conclusions: Updated results confirm etruma + mFOLFOX-6 was well tolerated in pts with mCRC without significant additive toxicity and was associated with disease control in heavily pretreated pts. Based on these encouraging data, a platform study (ARC-9) has been initiated to further explore this and other combinations in mCRC pts.

The role of site of metastatic resection (MR) in metastatic colorectal cancer (mCRC) patients (PTS): A mono-institutional cohort study.

e15558 Background: Approximately 50%-60% of CRC pts develop metastases, usually to liver and lung. When feasible, MR is the only potentially curative option in the multimodal management of mCRC pts. Few studies have compared survival outcomes based on different surgical sites with contrasting data. Hence, we retrospectively analyzed mCRC pts, underwent radical lung and/or liver resection at our Institution, investigating the impact of resection site on overall survival (OS). Methods: mCRC pts underwent radical liver (group 1), lung (group 2) or liver and lung (group 3) resection were included. The following variables were collected: age ( &gt; vs ≤ 65 years); gender (male vs female); primary tumor site (right vs left); synchronous vs metachronous; RAS/BRAF status; number (N) of MR (1, 2 or ≥3); chemotherapy treatment (No treatment vs Post-operative vs Peri-operative/pre-operative treatment) and chemotherapy regimen (5FU monotherapy, Oxaliplatin-based, Irinotecan-based regimen, FOLFOXIRI, Bevacizumab, Anti-EGFR). The association of MR site and OS was evaluated. Univariate and multivariate analyses for OS were performed. Results: A total of 191 mCRC pts underwent radical MR were included in the analysis: 112 (59%) pts in group 1, 38 pts (20 %) in group 2, 41 pts (21 %) in group 3. 145 (76%) pts had a left-sided tumor and 46 (24%) a right-sided tumor. Out of 156 evaluable pts, 73 (47%) pts harbored a RAS mutation, while out of 136 evaluable pts, 4 (3%) pts had a BRAF mutation. Regarding the N of MR, 125 pts (65%) underwent 1 radical MR, 43 (23%) pts 2 MR and 23 (12%) ≥3 MR. In the overall population, median OS was 77.2 months. According to MR site, median OS was 59.4, not reached (NR) and 99.1 months, in group 1, 2 and 3, respectively (p = 0.075). At the multivariate analysis no significant association with OS was shown for MR site, while the N of MR and RAS status were indipendently associated with OS. Median OS was 58.5, 97.7 months and NR in pts underwent 1, 2 and ≥3 MR, respectively (p = 0.02). Median OS was 58.5 and 83.1 months in RAS mutated and RAS wild-type pts, respectively (p = 0.12). Conclusions: Despite the limited number of pts and the retrospective nature of our study, these results confirmed that surgery represents the only option with curative intent for mCRC pts, independently of metastatic site (liver vs lung vs liver and lung). Based on our analysis, a higher number of MR is associated to a better outcome, and this could be explained with an accurate selection of patients that could benefit from multiple radical resections. Thus, a multidisciplinary approach is essential for the management of mCRC pts and surgery should be evaluated case by case and always performed when possible, even several times, independently of site of MR.

Pertuzumab plus trastuzumab and real-world standard of care (SOC) for patients (pts) with treatment refractory metastatic colorectal cancer (mCRC) with HER2 (ERBB2) amplification (amp) confirmed by tumor tissue or ctDNA analysis (TRIUMPH, EPOC1602).

3555 Background: HER2 amp occurs in 1-4% of mCRC pts. Two single arm phase 2 studies, HERACLES and MyPathway, showed efficacy for dual HER2-targeted therapy in pts with RAS wild type ( RAS wt) mCRC with HER2 amp detected in tumor tissue; however, efficacy for pts prospectively enrolled with HER2 amp identified in ctDNA is unknown. Furthermore, the efficacy of real-world non-HER2-targeted SOC for HER2 amplified RASwt mCRC pts is not clear. Methods: We conducted a phase 2 trial to evaluate the efficacy of pertuzumab (P) plus trastuzumab (T) in RASwt mCRC pts with HER2 amp centrally confirmed by tissue (IHC and/or FISH) and/or ctDNA (Guardant360) who had progressed on SOC including EGFR blockade. Pts received intravenous P (840 mg loading dose followed by 420 mg) and T (8 mg/kg loading dose followed by 6 mg/kg) every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: pts with HER2 amp in tissue (tissue+) or in ctDNA (ctDNA+). Efficacy of real-world non-HER2-targeted SOC for HER2 amplified RASwt mCRC pts was prospectively assessed in a concurrent registry: the SCRUM-Japan registry. Results: Among 75 pts screened, concordance of HER2 amp between tissue and ctDNA was 83%. The primary endpoint was met in each cohort of TRIUMPH, with confirmed ORR of 30% (95% CI 14-50%) in 27 tissue+ pts and 28% (12-49%) in 25 ctDNA+ pts. In contrast, ORR in first salvage SOC after EGFR blockade was 0% (0.0-24.7%) in the real-world cohort. Median progression free and overall survival were 4.0 months (1.4-5.6) and 10.1 months (4.5-16.5) in the tissue+ pts and 3.1 months (1.4-5.6) and 8.8 months (4.3-12.9) in the ctDNA+ pts. One pt withdrew due to an adverse event (grade 3 decreased ejection fraction), but no treatment related deaths occurred. In exploratory analyses, pts without ctDNA mutations of RAS/ BRAFV600/ PIK3CA/ HER2 were more likely to respond to P+T than those with a ctDNA mutation in at least one of these genes (ORR 44% vs. 0% in tissue+ and 37% vs. 0% in ctDNA+). Decreased ctDNA fraction and HER2 plasma copy number at 3 weeks after treatment initiation corresponded to P+T response. At least one actionable alteration emerged after progression in 16 (62%) of 26 pts with ctDNA results at both baseline and progression. Among 5 pts who achieved response and had ctDNA results at both time points, 4 pts acquired actionable alteration at progression. Conclusions: We demonstrate promising efficacy and safety of P+T for RASwt mCRC pts with HER2 amp in either tumor tissue or ctDNA. Our results show that complete ctDNA genotyping identifies pts most likely to benefit from dual HER2 blockade and can be used to monitor response and detect actionable resistance biomarkers. Clinical trial information: UMIN000027887 and UMIN000028058.

Concurrent BRAFV600E and BRCA mutations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Prevalence and case series of mCRC (pts) with prolonged overall survival (OS).

3561 Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically &lt;1 year. Despite use of multi-agent first-line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board database, we identified 3 consecutive mCRC pts with MSS/ BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had prolonged overall survival. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. Methods: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes ( BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis were BRAF V600E co-mutated with BRCA1 and BRCA2, separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation are described along with 3 consecutive cases of CRC patients, identified through the Inova Schar Cancer Institute (ISCI) molecular tumor board (MTB) registry, whom had prolonged OS. Results: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% having co-mutations of BRAF V600E and BRCA1/2. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of these occurred in MSS BRAF V600E. BRCA1 co-mutated was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p &lt;0.001 ). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, one confirmed germline and 2 somatic in origin, and had average gLOH of 21.4% with overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. Conclusions: Co-existence of BRAF V600E/ BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. Larger prospective clinical validation trials in this subset is warranted.[Table: see text]

Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial.

e15503 Background: Data on anti-angiogenic second line treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR drug are lacking and no validated biomarkers are available. We present the pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456), a biologically enriched, prospectively stratified phase 2 study assessing the aflibercept use in this setting. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy and candidates for second-line FOLFIRI/aflibercept are eligible for the DISTINCTIVE trial. Pts are prospectively allocated to a favorable (F) or unfavorable (U) prognostic group, according to Elisa-assessed baseline (BL) VEGFR2 plasma levels (PL). Other circulating angiogenic factors are evaluated at BL, first tumor assessment (TA1) and disease progression (PD). Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression). Sample size: 151 pts (one-sided test, α: 0.1, β: 0.2). Results: From 04/2018 to 06/2020, 73 pts were enrolled. Complete data from 44 pts were available for interim analysis. 33 pts (75%) achieved DCR (26 pts/59% SD, 7 pts/16% PR). Globally, median OS was 11.9 months (m) (95%CI 10 – 14.2). 24 (54.5%) pts were prospectively assigned to F group (VEGFR2 PL &gt; 4 ng/ml) and 20 (45.5%) to U group (VEGFR2 PL ≤4 ng/ml). OS in F group was 13.1 m (95%CI 9.6 – 14.2) vs 11.9 m (95%CI 6.8 – 11.9) in U group (HR 0.76 p = 0.6218). PFS was 9.8 m [95%CI 5.7 – 24.2] in F group vs 4.2 m [95%CI 2.5 – 14.2] in U group (HR 0.41 p = 0.0105). We also found preliminary correlation with PD as shown in table. Conclusions: Interim analysis showed high activity of FOLFIRI/aflibercept in RAS WT anti-EGFR pretreated mCRC pts. VEGFR2 showed promising ability to predict aflibercept efficacy. Our data on circulating angiogenic biomarkers are likely to further compose the landscape of anti-angiogenic activity in mCRC pts. Clinical trial information: NCT04252456. [Table: see text]

Impact of a metastatic site on circulating tumor DNA (ctDNA) analysis in patients (pts) with metastatic colorectal cancer (mCRC).

3554 Background: ctDNA genotyping has been used as an alternative to tissue genotyping for precision oncology. In mCRC, although low plasma RAS variant allelic frequencies (VAFs) and low concordance with tissue RAS tests have been reported in pts with lung-only metastasis (mets) (Kagawa Y. et al., Clin Cancer Res 2021), the association of ctDNA identified using the next-generation sequencing method with metastatic sites is still unknown. Methods: We investigated the association between metastatic site and ctDNA detection by using the Guardant360 (G360), a ctDNA assay which detects 74 gene alterations including mutations with the 95% of limit of detection of 0.2%, in mCRC pts with single organ mets in pts who had not received anti-EGFR therapy in the SCRUM-Japan GOZILA study. We also evaluated the correlations between the size/number of mets by CT and detected VAFs. Results: Of 1187 mCRC pts enrolled in GOZILA, 138 pts (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only mets) were eligible for this study. The concordance of RAS/ BRAF status between G360 and tissue in-vitro diagnostic tests were 93.9% in liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only mets. The median maximum VAF (maxVAF) corresponding to the highest ctDNA fraction and the median numbers of detected variants were 23.1% and 5 in liver-only, 6.0% and 5 in lymph node-only, 0.4% and 3 in peritoneum-only, and 0.4% and 3 in lung-only (all P&lt;0.001, Kruskal-Wallis test). A few pts with liver-only (2.0%) and lymph node-only mets (13.3%) had a maxVAF of &lt;0.2%, but maxVAF was more frequently &lt;0.2% in pts with lung-only (27.7%) or peritoneum-only mets (29.6%), especially in those with lung-only mets &lt;20 mm as the longest diameter and &lt;20 lesions (69.2%) or with peritoneum-only mets &lt;20 mm as the longest diameter (87.5%). Conclusions: Lung-only and peritoneum-only mets had significantly lower maxVAF and lower numbers of detected variants, suggesting lower detections of subclonal variants. To ensure the sufficient clinical performance in G360 assay, inclusion of pts with lung-only mets ≥20 mm of longest diameter and/or ≥20 lesions, and ≥20 mm of the longest diameter in pts with peritoneum-only mets may be required.[Table: see text]

Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC).

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.

Parameters associated with outcomes in pretreated MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Subgroup analysis of a prospective cohort.

3580 Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC. We aimed to evaluate clinical, pathological and molecular factors associated with progression-free survival (PFS) and overall survival (OS) in ICI-treated pretreated mCRC patients (pts). Methods: Pts are drawn from a prospective cohort of all patients treated with ICI for MSI/dMMR mCRC at Saint-Antoine Hospital, Paris, France. All MSI/dMMR mCRC pts with disease progression after ≥ 1 prior systemic treatment (fluoropyrimidine and oxaliplatin or irinotecan ± targeted therapy) were included. MSI/dMMR status was centrally reviewed. Lynch syndrome or sporadic status was determined according to MMR gene germline mutational testing, MLH1 methylation status and BRAFV600E mutation. PFS and objective response rate (ORR) were assessed using iRECIST criteria. The impact of Lynch syndrome on PFS was analyzed apart from the multivariate analysis due to the interaction with the BRAFV600E mutation status. Results: Of 130 included pts, 66 received anti-PD1 alone, 1 anti-PDL1 alone and 63 anti-PD1 plus anti-CTLA4. 71% have had at least 2 prior lines of treatment. 33 patients (25%) have BRAFV600Emutation (mt) and 49 (38%) RASmt. The ORR for the whole population was 62.8 % IC95% [53.8; 71.1]. Median follow-up was 21.0 months, median PFS and OS were not reached. Results of PFS unadjusted and adjusted analysis are displayed in the table. BRAFV600E and RAS mutation were not associated with PFS and OS in multivariate analyses. After adjustment for the treatment type, Hazard Ratio (HR) for PFS between patients with proven Lynch syndrome (N=44) and patients with proven sporadic tumors (n= 44) was 0.57 (95%IC 0.26 -1.26). Conclusions: In this cohort, main known clinical, pathological and molecular factors do not influence the efficacy of ICI in pre-treated MSI/dMMR mCRC.[Table: see text]