Morris, Van K.

LBA3500 Background: BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses. Methods: Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC). Results: 637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR=0.53 (95% CI 0.407, 0.677; P<0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR=0.49 (95% CI 0.375, 0.632; P<0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC. Clinical trial information: NCT04607421 . ECn=158 EC+mFOLFOX6n=236 SOCn=243 EC+mFOLFOX6vs SOCHR (95% CI)P-value a Median PFS b , mo (95% CI) 6.8(5.7, 8.3) 12.8(11.2, 15.9) 7.1(6.8, 8.5) 0.53 (0.407, 0.677) <0.0001 Median OS, mo (95% CI) 19.5(17.6, 22.5) 30.3(21.7, NE) 15.1(13.7, 17.7) 0.49 (0.375, 0.632)<0.0001 ORR, b % (95% CI) 45.6(38.0, 53.3) 65.7(59.4, 71.4) 37.4(31.6, 43.7) Median DOR b , mo (95% CI) c 7.0 (4.2, 11.6) 13.9 (10.9, 18.5) 10.8 (7.6, 13.4) DOR b ≥6 mo, n (%) c 29 (40.3) 110 (71.0) 38 (41.8) DOR b ≥12 mo, n (%) c 15 (20.8) 54 (34.8) 16 (17.6) Median time to response, b wk (range) c 6.6(4.3-86.4) 7.0(5.1-103.6) 7.3 (5.4-48.0) a 1-sided stratified log rank test. b By BICR. c Responders: n=72, n=155, and n=91. DOR, duration of response.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgement. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard-of-care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only). PURPOSE To provide evidence-based guidance for clinicians who treat patients with stage I-III anal cancer. METHODS A systematic review of the literature conducted by the Minnesota Evidence-based Practice Center provided the evidence base for this guideline. An ASCO Expert Panel reviewed this evidence and came to consensus on a set of evidence-based recommendations. RESULTS The systematic review contained three randomized controlled trials and three nonrandomized studies of interventions that were relevant to the guideline topic and informed the recommendations. RECOMMENDATIONS Mitomycin-C (MMC) with a fluoropyrimidine (fluorouracil [FU] or capecitabine) is recommended as the radiosensitizing component of chemoradiation (CRT) for anal cancer; the Expert Panel recognizes that capecitabine is often used as an orally administered alternative to FU and is currently being used in ongoing clinical trials. Cisplatin with FU is an additional chemotherapy combination that may be recommended as radiosensitizing chemotherapy. Because of the myelosuppression associated with MMC, the preferable regimen for patients with immunosuppression is cisplatin and FU. Cisplatin is not recommended for patients with renal dysfunction, significant neuropathy, or hearing loss, and there is no evidence to recommend substituting carboplatin for cisplatin. Dose and schedule options for recommended chemotherapy agents are included within the full text of the guideline. Routine induction chemotherapy before CRT and additional chemotherapy after CRT are not recommended for patients with localized anal cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.

4108 Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p<0.0001 Chi-square: 70.33). Additionally, in patients with radiologically measurable active metastatic disease, ctDNA detection rate was 100%. On the contrary, patients with advanced/metastatic disease who had partial response to treatment or no evidence of disease (NED) showed 28.5% and 19.2% of ctDNA-positivity, respectively. Conclusions: This is the first large, real-world study reporting on the results from a clinically validated MRD assay. For the first time we delineate MRD rates and quantify ctDNA concentration in patients with early-stage and advanced CRC. Furthermore, we provide an initial readout that effective ongoing treatment in patients with CRC may be correlated with ctDNA clearance. Ongoing analysis expanded to a cohort of 1200 clinical cases including correlation with genomic and serial testing will be presented. [Table: see text]

4047 Background: BRAFV600E mutations occur in fewer than 10% of all patients (pts) with metastatic colorectal cancer (mCRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for pts with BRAFV600E mCRC in general are poor. Characteristics distinguishing pts with BRAFV600E mCRC with favorable versus unfavorable outcomes have not been well annotated. Methods: Records of 188 pts with BRAFV600E mCRC evaluated at MD Anderson Cancer Center between 3/2010-1/2020 were reviewed. Pts with the shortest and longest metastatic survival (N = 25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing. Results: Median metastatic survival differed between the 2 BRAFV600E mCRC populations (8.6 vs 84 months, p < .0001). Pts with poor survival more commonly had primary tumors arising from the hepatic flexure/proximal transverse colon (44% vs 16%, p = .04) and more frequent hepatic involvement (75% vs 28%, p = .001). Pts with favorable survival were more likely to develop metachronous metastases (52% vs 16%, p = .01), have fewer distant organ involvement (median 1 vs 2, p = .02), and undergo definitive locoregional therapy to metastatic disease (44% vs 0%, p = .01). Microsatellite instability (36% vs 4%, p = .008) and a history of tobacco use (44% vs 16%, p = .04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies (5/25) and immunotherapy (3/25) were noted in the favorable group. Conclusions: Pts with BRAFV600E mCRC can achieve excellent long-term survival which belies conventional context and is driven by locoregional and systemic treatment options alike. Anatomic localization of the primary tumor and prior exposures may highlight environmental influences on tumor biology which account for the clinical heterogeneity of pts with BRAFV600E mCRC.

Abstract Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their colorectal cancer. Consequently, many patients present with metastatic colorectal cancer, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of colorectal cancer tumors and are associated with uninhibited cell proliferation, reduced apoptosis, and resistance to standard therapeutic options. In colorectal cancer, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared with tumors with wild-type BRAF. Success in treating other BRAFV600E-mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic colorectal cancer. Consequently, combination therapy with inhibitors of BRAF, MEK, and EGFR, which overcomes the innate treatment-resistant characteristics of BRAFV600E-mutant colorectal cancer, is now recommended by treatment guidelines.

AbstractBackground and ObjectivesPrecision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well‐described. This study aims to determine the concordance of genomic profiles between primary CRC and PM.MethodsPatients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild‐type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant.ResultsThirty‐eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti‐epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes.ConclusionsBecause high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS‐mutant PM should be considered, particularly among patients previously treated with anti‐EGFR therapy.

e15055 Background: An increasing number of pt and tumor c have predictive and prognostic implications in mCRC. However, there is no consensus on their reporting in trial results. Methods: Pt c and SF from 136 phase III trials of systemic therapies (Rx) in mCRC published between 1988 and 2018 (68,326 pts) were collected. Trials were also grouped per publication date (G1: 1988-97; G2: 98 – 2007; G3: 08-18). Patterns of reporting and trends across G were evaluated. Results: Pt c consistently reported were performance status, PS (98.5%), age (92.6%) and gender (90.4%); race (20.6%) & weight/BMI/BSA were not (13.2%). Tumor c frequently reported were metastatic (met) spread (70.6%) while time intervals related to disease course (25%) and synchronous met vs not (19.1%) were omitted. Of note, primary site was largely reported as colon vs rectum (69%) and sidedness or anatomical location was discernable only in 10.3%. Prior Rx reporting focused on chemo (58.5%) with radiation and surgery and reported in 34% & 28.7%. Reporting of prognostic factors was variable and limited: histology grade CEA, alk phos, LDH (range 10.3-15.4%). Only 11.8% of trials reported genomic factors - KRAS MT was included in all with BRAF MT in 4.4%. Of 140 trials used for SF analysis, 115 had ≥ 1 (range 1-7). Common SF were PS (60%), geography /institution (55.7%). Prior Rx (27%), met spread (24.3%) were sometimes used while primary site (7.8%), genomic factors (6.1%) rarely were. Trends across G are per Table. Conclusions: There is marked inconsistency in pt c & SF reporting in mCRC trials. Consensus guidelines will aid in standardization of trial interpretation and future meta-analyses; and will need to be updated based on emerging data. [Table: see text]