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Background No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. Methods Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. Results Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. Conclusions Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.

Introduction Patients with gastrointestinal (GI) cancers have an increased risk of serious complications and death from SARS-CoV-2 infection. The immunogenicity of vaccines in patients with GI cancers receiving anti-cancer therapies is unclear. We conducted a prospective study to evaluate the prevalence of neutralizing antibodies in a cohort of GI cancer patients receiving chemotherapy following SARS-CoV-2 vaccination. Materials and Methods Between September 2020 and April 2021, patients with cancer undergoing chemotherapy were enrolled. At baseline (day 0), days 28, 56, and 84, we assessed serum antibodies to SARS-CoV-2 spike (anti-S) and anti-nucleocapsid (anti-NP) and concomitantly assessed virus neutralization using a pseudovirus neutralization assay. Patients received either the Pfizer/BioNTech BNT162b2, or the Oxford/AstraZeneca ChAdOx1 vaccine. Results All 152 patients enrolled had a prior diagnosis of cancer; colorectal (n = 80, 52.6%), oesophagogastric (n = 38, 25.0%), and hepato pancreatic biliary (n = 22, 12.5%). Nearly all were receiving systemic anti-cancer therapy (99.3%). Of the 51 patients who did not receive a vaccination prior to, or during the study, 5 patients had detectable anti-NP antibodies. Ninety-nine patients received at least one dose of vaccine prior to, or during the study. Within 19 days following the first dose of vaccine, 30.0% had anti-S detected in serum which increased to 70.2% at days 20-39. In the 19 days following a second dose, anti-S positivity was 84.2% (32/38). However, pseudovirus neutralization titers (pVNT80) decreased from days 20 to 39. Conclusion Despite the immunosuppressive effects of chemotherapy, 2 doses of SARS-CoV-2 vaccines are able to elicit a protective immune response in patients’ ongoing treatment for gastrointestinal cancers. Decreases in pseudoviral neutralization were observed after 20-39 days, re-affirming the current recommendation for vaccine booster doses. Clinical Trial Registration Number NCT04427280.

Background Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. Methods Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. Results Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for DPYD heterozygous carriers and 93.2% (42.9–100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). Conclusions Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

Background Circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK’s first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS). Methods We are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022. Discussion The trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it. Trial registration NCT04050345.

International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p

Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of HER2 gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. Although limited progress was made in the decade following ToGA, there is now an abundance of novel therapeutic approaches undergoing investigation in parallel. Additionally, new data from randomised trials have indicated efficacy of the antibody-drug conjugate trastuzumab deruxtecan in chemorefractory patients and increased responses with the addition of first-line immune checkpoint blockade to trastuzumab and chemotherapy. This review will outline the data supporting HER2 targeting in gastric cancers, discuss mechanisms of response and resistance to HER2-directed therapies and summarise the emerging therapies under clinical evaluation that may evolve the way we manage this subset of gastric cancers in the future.

Background: There is a lack of large-scale randomised data evaluating the impact of sex and age in patients undergoing chemotherapy followed by potentially curative surgery for oesophagogastric cancer. Patients and methods: Individual patient data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival analysis, hazard ratios (HRs) were calculated for patients aged

BRAF V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. Significance: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care. See related commentary by Ribas and Lo, p. 640. This article is highlighted in the In This Issue feature, p. 627

Purpose: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer. Experimental Design: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan–Meier method and Cox regression. Results: ctDNA detection rates were: 74% (n = 35/47) pretreatment, 21% (n = 10/47) mid CRT, 21% (n = 10/47) after completing CRT, and 13% (n = 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P = 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4–21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2–11.7; P = 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3–40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of ≥0.07% mid CRT or ≥0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P = 0.001). Conclusions: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.

169 Background: Absence of post-operative ctDNA identifies resected CRC pts with low recurrence risk for potential adjuvant chemotherapy (ACT) de-escalation. We present the largest resected CRC cohort with plasma-only MRD detection, facilitating fast turnaround times, rapid treatment decisions and circumventing the need for tissue analysis, a challenge in real world practice. Methods: TRACC included pts with stage I-III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and post-surgery, after completion of ACT, every 3m (yr 1), every 6m (yrs 2/3) with CT annually for 3yrs. Guardant’s Reveal assay evaluated genomic/methylation signals. The primary end point was 2 year recurrence free survival (RFS) by 3-12wk post-operative ctDNA detection. Secondary end points included landmark RFS (3-12wk post-definitive treatment; surgery/ACT), longitudinal (on/after landmark timepoint) sensitivity/specificity and lead time to recurrence. Survival outcomes were calculated using Cox regression. Results: Dec 16 - Aug 22, 1203 pts enrolled. Plasma samples (n = 997) from 214 pts were analysed. 143 pts were evaluable for the primary end point; 92 (64.3%) colon, 51 (35.7%) rectal cancer; 2 (1.4%) stage I, 64 (44.8%) stage II, 77 (53.8%) stage III. Median follow up was 30.4m (95% CI: 29.6-31.7). 2 year RFS is shown in the table. No association between CEA and ctDNA positivity was seen. 14 pts were landmark ctDNA positive, 8 of whom did not relapse. In-depth genomic review revealed true positives (positive in tissue), some with limited follow up and suspected false positives due to putative genomic (i.e., CHIP) or methylation calls. We observed dynamic genomic/methylation changes demonstrating cancer evolution over time. 9 landmark ctDNA negative pts relapsed/died; 5 had longitudinal samples available of whom 4 remained negative during follow up. Relapse sites included lung (n = 2), liver (n = 1) and nodal (n = 1). Longitudinal sensitivity and specificity were 50.0% (95% CI: 27.2-72.8) and 85.9% (95% CI: 78.9-91.3) respectively with a negative predictive value (NPV) of 92.1% (95% CI: 85.9-96.1) and median lead time from ctDNA detection to radiological recurrence of 5.2m (IQR: 3.2, 8.0) (n = 9). Conclusions: Plasma-only genomic/methylation MRD detection with longitudinal sampling can predict recurrence in pts with stage I-III CRC without need for tissue analysis. NPV is high supporting an ACT de-escalation strategy in post-operative ctDNA negative pts, now investigated in the ongoing UK TRACC C randomised study (NCT04050345). Clinical trial information: NCT04050345 . [Table: see text]

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

446 Background: ICONIC evaluated 4+4 cycles of FLOT-A (2-weekly standard FLOT with 10mg/kg of the anti-PDL1 antibody avelumab) for perioperative treatment of early-stage OGA. We report R0 resection rates, pathologic complete response rates (pCR), pathologic tumour regression grades (TRG) according to Mandard classification and progression free survival (PFS) data in the modified intention to treat population (mITT), and translational analyses. Methods: ICONIC is a single-arm phase II trial of FLOT-A in patients (pts) with ≥cT2-4 or N+ OGA. The pCR rate in surgical specimens was the primary endpoint. Response evaluation according to Mandard, R0 rates and PFS were among secondary endpoints. PD-L1 expression was assessed according to the combined positive score (CPS) with the 22C3 pharmDx kit. Results: The trial closed early after the pCR rate was 15% (95% CI: 49%-83%) once 34 pts in the mITT population (defined as pts who had 1-4 cycles FLOT-A and surgery) as the pre-specified aim to demonstrate a pCR rate of 25% in 40 pts was unlikely to be met. Baseline characteristics of the mITT population were: median age 64y, 79% male, 79% OG junction, 6% oesophageal, 15% stomach, 65% poorly differentiated, 79% T3/4, 59% N+. 91% of pts received all 4 pre-operative cycles and 97% of pts achieved R0 resections. PDL1 CPS ≥1 and CPS ≥5 were nevertheless associated with increased TRG3 and decreased TRG4/5 rates. 3/34 pts (9%) had hypermutated/MMRd tumours and after their exclusion, the association of higher CPS with better TRG3 and decreased TRG4/5 remained. With a median follow up duration of 15.8 months the 12-month PFS was 93.1% (95% CI: 75.1%-98.2%) which is promising compared to historic results with peri-operative FLOT. Conclusions: Although FLOT-A failed to increase pCR rates to 25%, there is a trend towards higher TRG3 and lower TRG4/5 in pts with PDL1 CPS≥1 and CPS≥5 and promising PFS indicate activity of immunotherapy in combination with FLOT chemotherapy. Translational and biomarker analyses by exome- and RNA-sequencing, and multiplex immune cell staining are ongoing and will be reported. Clinical trial information: NCT03399071 . [Table: see text]

419 Background: A predictive biomarker for resistance to trastuzumab in HER2 positive oesophago-gastric cancer would refine patient selection. Our preclinical studies suggest that patients with HIGH baseline plasma miR-148a-3p levels will experience shorter Overall Survival (OS), Progression Free Survival (PFS), and worse Progression Free Rates (PFR) than those with LOW plasma miR-148a-3p levels. Methods: This sub-study is a prospective biomarker analysis of baseline plasma samples for HER2 positive advanced oesophago-gastric cancer patients registered within Arm B1 of the Phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182). All HER2 positive patients assessable for clinical response and miR signatures were included. Copies of miR-148a-3p and miR-16 per ml of plasma were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR). OS as primary endpoint for miR-148a-3p LOW (≤median) versus HIGH (>median) was analysed using Kaplan-Meier curves and Cox model regression. Secondary endpoints were PFS and PFR. OS and PFS are from start of 1st line therapy; PFR are from start of maintenance trastuzumab. Sensitivity analysis normalised miR-148a-3p to miR-16. Results: Of 63 patients with analysable lab samples and available survival data, normalisation was possible for 41 patients. Median follow-up was 38 months. There was no statistically significant relationship between OS and miR-148-3p copies/μl of ddPCR reaction LOW versus HIGH (n= 62, Hazard Ratio (HR) 0.98, p=0.933), PFS (n=62, HR 1.08, p=0.759) or PFR (n=31, Odds Radio (OR) 0.67, p=0.577). Normalised miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in PFR at 3 months (n=23, OR=0.11, p=0.027) but no difference in OS or PFS. A model adjusting for primary tumour site, metastatic disease and number of sites demonstrated a statistically significant difference in PFR at 3 months (aOR=0.03, p=0.029). Conclusions: Patients with HIGH NmiR-148-3p have 0.03 times the odds of being progression-free at 3 months than patients with LOW NmiR-148a-3p in this population, when adjusted for key factors. Limitations include small sample size and normalisation. Clinical trial information: NCT02678182 . [Table: see text]

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome., Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines .

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines .

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.

293 Background: NET-02 was a multi-centre, randomised (1:1), non-comparative phase II trial of nal-IRI/5-FU/folinic acid (ARM A) or docetaxel (ARM B) in pts with progressive PD-EP-NEC, aimed at selecting a treatment for evaluation in a phase III trial. Primary analysis (N = 58) showed ARM A, but not ARM B, achieved the target 6-month progression-free survival rate primary endpoint (McNamara et al. ASCO 2022). HRQoL was a secondary endpoint in NET-02. Methods: HRQoL was assessed using the EORTC QLQ-C30 and GINET21 (at baseline (BL), 6-weekly intervals and at disease progression). The mean change from BL was estimated for each scale by timepoint and treatment arm. Results are presented where there were ≥4 responses per time point. Scores were considered stable if they did not change by > 10 points from BL. The mean BL C30 scores for all pts were compared to United Kingdom (UK) population normative C30 data using a 2-sample t-test. Results: Fifty-four of 58 pts (93%) completed a BL questionnaire; of these, 39 (72%) completed ≥1 post-BL questionnaire, with 21 (51%) completing questionnaires at progression. Global health status (GHS) and all functional scales in ARM A remained stable from BL to intervals pre-progression, with a sustained improvement in role functioning observed post-BL. In ARM B, GHS and all C30 functional scales decreased by > 10 points between BL and week 18 (worsening of QoL). Both arms had a > 10-point increase from BL in constipation and diarrhoea in ≥1 post-BL time point. In ARM A, pain, insomnia and financial problems decreased from BL. No C30 symptom scales in ARM B were consistently lower post-BL. Patterns of change in GINET21 mean score were similar in both arms: body image, disease-related worries, information/communication, sexual function and social function all had a > 10-point reduction in score from BL (indicating improvement in symptoms/problems); endocrine and gastrointestinal symptoms remained stable; muscle/bone pain varied across time points, initially showing a reduction in pain followed by an increase, compared to BL. In comparison to the UK C30 norms (BL all pts), 11 of 15 C30 scales did not significantly differ (P > 0.05). Mean scores for fatigue and appetite loss were significantly higher than UK C30 norms (worse symptoms in pts from NET-02) (P = 0.03, P = 0.0003 respectively). However, emotional functioning and GHS were significantly better in pts from NET-02 (P = 0.001, P = 0.03 respectively). Role and social functioning were lower in pts from NET-02 (both P = 0.06) (poorer level of functioning). Conclusions: HRQoL was maintained and potentially improved with nal-IRI/5-FU/folinic acid, but not docetaxel. Compared to the UK general population, BL QoL did not substantially differ in pts from NET-02. Clinical trial information: NCT03837977.

Pancreatic cancer (PC) presents extremely aggressive tumours and is associated with poor survival. This is attributed to the unique features of the tumour microenvironment (TME), which is known to create a dense stromal formation and poorly immunogenic condition. In particular, the TME of PC, including the stromal cells and extracellular matrix, plays an essential role in the progression and chemoresistance of PC. Consequently, several promising agents that target key components of the stroma have already been developed and are currently in multiple stages of clinical trials. Therefore, the authors review the latest available evidence on novel stroma-targeting approaches, highlighting the potential impact of the stroma as a key component of the TME in PC.

The MYC proto-oncogene is among the most commonly dysregulated genes in human cancers. We report screening data from the iMYC trial, an ongoing phase II study assessing ibrutinib monotherapy in advanced pretreated MYC- and/or HER2-amplified oesophagogastric cancer, representing the first attempt to prospectively identify MYC amplifications in this tumour type for the purposes of therapeutic targeting.Screening utilising a fluorescent in situ hybridisation (FISH) assay for assessment of tumour MYC amplification has been instituted. An experimental digital droplet polymerase chain reaction (ddPCR) assay to assess MYC amplification in both tumour and circulating-tumour (ct)DNA has been developed and investigated.One hundred thirty-five archival tumour specimens have undergone successful FISH analysis with 23% displaying evidence of MYC amplification. Intertumour heterogeneity was observed, with the percentage of cancer cells harbouring MYC amplification ranging widely between samples (median 51%, range 11-94%). Intratumoural clonal diversity of MYC amplification was also observed, with a significant degree of variance in amplification ratios (Bartlett's test for equal variance p 0.001), and an association between greater variance in MYC amplification and improved outcome with prior first-line chemotherapy. ddPCR was most accurate in quantifying MYC amplification in tumour-derived DNA from cases with a high proportion (70%) of amplified cells within the tumour specimen but was not reliable in samples containing a low proportion of amplified cells or in ctDNA.Our results illustrate the utility of FISH to assess MYC amplification prospectively for a biomarker-selected trial by providing reliable and reproducible results in real time, with a high degree of heterogeneity of MYC amplification observed. We show that ddPCR can potentially detect high-level MYC amplifications in tumour tissue.

Background Sex contributes to interpatient variability of chemotherapy metabolism and dose response, potentially influencing both efficacy and toxicity; however, comparative data on its effect on oesophagogastric cancer are lacking. Patients and methods Data for patients with advanced oesophagogastric cancer randomised to comparable first-line chemotherapy regimens within four United Kingdom prospective trials were pooled, and key demographic and outcome measures were compared between males and females. Results A total of 1654 patients were included: 1328 (80.3%) males and 326 (19.7%) females. Female patients were younger, had a significantly higher proportion of gastric tumours as opposed to junctional or oesophageal tumours and experienced significantly higher rates of a number of toxicities including nausea and vomiting, diarrhoea, stomatitis and alopecia. When adjusting for potential confounding factors, the risk of female patients experiencing grade ≥III gastrointestinal toxicity was greater (adjusted odds ratio = 1.50; 95% confidence interval = 1.07–2.12). Females also had a significantly higher incidence of serious adverse events on treatment and received comparatively less cycles of chemotherapy overall than males. Conclusions This represents the largest pooled analysis of the effect of sex on chemotherapy outcome and toxicity in advanced oesophagogastric cancer. The differential toxicity and adverse event rates observed suggest that sex may be an important modulator of treatment tolerability and safety in this tumour type.

Gastrointestinal cancers are very common cancers with colorectal being the fourth most common type, gastric the sixth, and esophageal the tenth. Although recent advances have been made in management including incorporation of antiangiogenic, anti-EGFR, and anti-HER2 directed therapies, overall their prognosis remains poor. Anti-PD-1 therapy with nivolumab and pembrolizumab are licensed for advanced chemorefractory gastroesophageal cancer and many other checkpoint inhibitor therapies are being assessed alone and in combination in these diseases. One of the challenges posed in assessing response to immunotherapy treatment is the phenomenon of pseudoprogression. This phenomenon, which is well described in patients with malignant melanoma is most frequently described as a size increase of contrast enhancing lesions or appearance of new lesions that stabilize or reduce in size with time. Most other solid tumors have a low incidence of pseudoprogression although cases have been reported for lung, head, and neck cancer and a range of gliomas. Herein we present 6 cases of patients with gastrointestinal cancers who were treated with anti-PD1 (programmed cell death) and anti-PD-L1 (programmed cell death ligand-1) antibodies, and experience pseudoprogression.

Background There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. Methods A 2-step matching process generated RW cohorts from Flatiron Health’s oncology database (January 1, 2011–April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan–Meier analysis from last treatment until death. Results Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. Conclusions We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

Ramucirumab is a fully humanized monoclonal antibody directed selectively at VEGFR-2 – a key player in the VEGF orchestra and angiogenic process. It has demonstrated clinical efficacy and a favorable safety profile in the treatment of a number of malignancies including gastric, lung, urothelial, colorectal and, most recently, advanced liver cancer. This article describes the recent Phase III trial results of ramucirumab in patients with hepatocellular carcinoma, including safety data and patient-reported outcomes, with particular emphasis on efficacy data in the patient population with baseline α-fetoprotein levels ≥400 ng/ml, traditionally considered a poor prognostic group.

Background FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. Methods We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. Results We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. Conclusions This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]

Purpose BRAFV600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma. We sought to determine the activity of vemurafenib, a selective inhibitor of BRAFV600, in patients with gliomas that harbor this mutation. Patients and Methods The VE-BASKET study was an open-label, nonrandomized, multicohort study for BRAFV600-mutant nonmelanoma cancers. Patients with BRAFV600-mutant glioma received vemurafenib 960 mg twice per day continuously until disease progression, withdrawal, or intolerable adverse effects. Key end points included confirmed objective response rate by RECIST version 1.1, progression-free survival, overall survival, and safety. Results Twenty-four patients (median age, 32 years; 18 female and six male patients) with glioma, including malignant diffuse glioma (n = 11; six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1), were treated. Confirmed objective response rate was 25% (95% CI, 10% to 47%) and median progression-free survival was 5.5 months (95% CI, 3.7 to 9.6 months). In malignant diffuse glioma, best response included one partial response and five patients with stable disease, two of whom had disease stabilization that lasted more than 1 year. In PXA, best response included one complete response, two partial responses, and three patients with stable disease. Additional partial responses were observed in patients with pilocytic astrocytoma and anaplastic ganglioglioma (one each). The safety profile of vemurafenib was generally consistent with that of previously published studies. Conclusion Vemurafenib demonstrated evidence of durable antitumor activity in some patients with BRAFV600-mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.

Importance Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors. Objective To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received. Design, setting, and participants This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively. Interventions Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062. Main outcomes and measures Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing. Results At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy. Conclusions and relevance Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received. Trial registration ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.

Background In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). Methods Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. Results 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). Conclusion In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. Trial registration ClinicalTrials.gov, NCT02370498

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR012) of the Conference Proceedings. Citation Format: Benjamin R. Challoner, Andrew Woolston, David Lau, Marta Buzzetti, Louise J. Barber, Tom Lund, Harold B. Sansano, Katharina von Loga, Héctor Lázare-Iglesias, Ruwaida Begum, Richard Crux, David Cunningham, Ian Chau, Naureen Starling, Juan Ruiz-Bañobre, Tony Dhillon, Marco Gerlinger. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A002.

Mismatch repair deficient (MMRd) CRCs have high mutation/neo-antigen loads, leading to high immunogenicity and good immunotherapy response rates. We reasoned that the MMRd hypermutator phenotype should also promote intratumor heterogeneity (ITH) and evolvability; and investigated the genetic and immunological co-evolution in 69 regions from 6 localized and 13 metastatic MMRd CRCs by multi-region DNA-, RNA-sequencing and immunohistochemistry. All tumors had high truncal mutation loads (median: 44 mutations in 191 sequenced genes; whole exome equivalent: 1870 mutations). A median of 16.1% mutations per region were heterogeneous, indicating pervasive ITH. Phylogenetic analyses showed that metastases had diverged before subclonal diversification of the primary tumor in 75% of assessable cases. Thus, the ability to metastasize was frequently acquired early during tumor evolution. Driver aberrations evolved with a clear hierarchy: those in the WNT and RTK-MAPK pathways and in TGFbR-family members were almost always truncal (87.0%, 86.4% and 83.7%), indicating a critical role for cancer initiation. In contrast, genetic aberrations that are known to confer immune evasion (IE) were predominantly subclonal (71.4%) and parallel evolution of IE drivers occurred in 4/6 tumors that harboured any subclonal IE driver. This substantiates immune selection pressure as the main driver of Darwinian evolution during tumor progression. These IE drivers are known to confer resistance to checkpoint-inhibitor immunotherapy. ITH therefore needs to be addressed for predictive biomarker development. We quantified CD8 T-cell infiltrates as a surrogate measure of tumor immunogenicity; distinguishing tumors with low CD8 T-cell infiltrates (mean: 3.9% T-cells of all nucleated cells) and those with high infiltrates (mean: 12.2%). T-cell infiltrates showed high ITH in the latter group. This suggested a tumor-intrinsic setpoint, accompanied by marked variability in tumors with dense infiltrates. T-cell densities did not correlate with truncal mutation loads or heterogeneity metrics, questioning how immunogenicity is regulated. Phylogenetic analysis defined three patterns of IE evolution: tumors with subclonal, with pan-tumor, or without any identifiable IE drivers. CD8 T-cell abundance was highest in tumors with subclonal IE, supporting selection pressure from high CD8 T-cell infiltrates as the proximate cause for IE evolution. Tumors with pan-tumor IE showed low CD8 T-cell infiltrates. Surprisingly, tumors without IE drivers had the lowest CD8 T-cell abundance, indicating an alternative mechanism of immune escape. Low densities of CD8 T-cells at the tumor margin and low expression of T-cell chemo-attractants suggested impaired T-cell recruitment in these. Together, we show that immune recognition is a major driver of Darwinian evolution in MMRd CRCs and that immune infiltrates and IE drivers co-evolve interdependently. Whether sensitivity to checkpoint-inhibitor immunotherapy differs between the three phylogenetic MMRd CRC subtypes needs to be assessed in clinical trials. Citation Format: Benjamin R. Challoner, Andrew Woolston, David Lau, Marta Buzzetti, Louise J. Barber, Tom Lund, Harold B. Sansano, Katharina von Loga, Héctor Lázare-Iglesias, Ruwaida Begum, Richard Crux, David Cunningham, Ian Chau, Naureen Starling, Juan Ruiz-Bañobre, Tony Dhillon, Marco Gerlinger. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR012.

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (&ge, 18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score &ge, 1) in 19 and -negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%, PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months, PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months, PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-na&iuml, ve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors.

Background Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses. Patients and Methods All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis. Results A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 μm and tmour content of >20%, respectively. Conclusion The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.

Purpose:In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors.Patients and Methods:In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1–staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression.Results:There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1–positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1–positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1–negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI.Conclusions:This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.See related commentary by Moutafi and Rimm, p. 3812

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

SUMMARYAnti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis, a transient cetuximab-induced increase in mutagenesis, contributes in patients is unknown. We investigated this in exome sequencing data of 42 baseline and progression biopsies from cetuximab treated CRCs. Mutation loads did not increase from baseline to progression. Evidence for a contribution of cetuximab-induced mutagenesis was limited. However, the mutational Signature 17 was a key contributer of specific KRAS/NRAS and EGFR driver mutations that are common at acquired resistance. Signature 17 activity before treatment predicted shorter progression free survival. This demonstrates the utility of mutational signatures to predict cancer drug resistance evolution.SIGNIFICANCEDrug resistance evolution occurs ubiquitously in solid tumours during treatment with targeted drugs. Biomarkers that can be assessed prior to treatment to predict the time to resistance evolution and the genetic resistance mechanisms that will evolve have not been described. We identified the mutational Signature 17 as the first candidate biomarker that predicts shorter time to progression and several specific KRAS/NRAS and EGFR mutations that will likely evolve in CRCs during cetuximab treatment. Understanding the mutational mechanism underlying Signature 17 may open opportunities to delay resistance acquisition. The potential of mutational signatures to predict resistance to a broader range of drugs in other tumor types should be assessed.

Background 10%–15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or POLE exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show POLE-mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or POLE mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS). Methods We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or POLE exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. Trial registration number NCT03827044

Contains fulltext : 225337.pdf (Publisher’s version ) (Closed access) Malignant dysphagia is the most common symptom in advanced oesogastric cancers patients. Relief of dysphagia allows quality of life improvement, nutritional replenishment and potentially improves prognosis. Chemotherapy alone is effective and should be prioritised in patients with metastatic disease a good performance status, and its impact on dysphagia should be determined before further interventions are planned. Regarding local treatments, the insertion of a covered self-expandable metallic stent is the most commonly used alternative, as it allows for the rapid relief of severe dysphagia. Although several randomised trials have highlighted the role of oesophageal brachytherapy, this technique is often not easily accessible. Contemporary trials are ongoing to better define the role of external radiation therapy. While awaiting these results, external radiation therapy can be considered as a second-best option for patients with a life-expectancy > 3 months. It is important to offer nutritional support and to integrate quality of life measures in the palliative management of dysphagia. This multidisciplinary international position paper aims to propose a decision-making process and highlight randomised trials for the management of malignant dysphagia in metastatic oesogastric cancer patients.

Background Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab. Patients and methods Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted. Results In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings. Conclusions Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient–clinician discussions about the benefit–risk profile of this therapy. Trial registration number NCT01140347 ; NCT02435433 , NCT02435433 .

TPS374 Background: The current standard of care for patients (pts) diagnosed with unresectable, locally advanced esophageal squamous-cell carcinoma (ESCC) is definitive platinum-based concurrent chemoradiotherapy (dCRT). However, ESCC has poor prognosis, with more than half of tumors reoccurring after dCRT (Smyth et al. Nat Rev Dis Primers 2017), highlighting the need for additional therapy options in this setting. Cancer immunotherapies have demonstrated activity in ESCC, and targeted inhibition of the PD-L1/PD-1 pathway may be further amplified using novel anti-TIGIT agents such as tiragolumab. In preclinical mouse models, concomitant blockade of PD-L1/PD-1 and TIGIT pathways demonstrated prolonged survival over the respective single-agents. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) resulted in a clinically meaningful improvement in PFS and higher ORR vs atezolizumab alone (31.3 vs 16.2%) in first-line pts with PD-L1+ (TPS ≥1%) metastatic NSCLC. SKYSCRAPER-07 (NCT04543617) will determine if tiragolumab plus atezolizumab combination therapy provides superior clinical benefit to atezolizumab monotherapy or placebo in pts with unresectable ESCC whose cancers have not progressed following dCRT. We hypothesize that combination therapy will prolong PFS and OS compared with placebo in this setting. Methods: Eligible pts (≥18 years) must have unresectable ESCC, without progressive disease (PD) after platinum-based dCRT (according to regional oncology guidelines for ESCC); ECOG PS 0–1; no prior treatment with any immune checkpoint inhibitor. Approximately 750 pts will be randomized 1:1:1 to either Arm A (tiragolumab 600mg + atezolizumab 1200mg IV Q3W), Arm B (atezolizumab 1200mg + placebo IV Q3W) or Arm C (double placebo IV Q3W). Treatment will continue for up to 17 cycles of 21 days, or until unacceptable toxicity or investigator-assessed radiographic PD (per RECIST v1.1). Stratification factors include geographic region (Asia vs rest of world), PD-L1 expression and staging prior to dCRT (II vs III vs IV). Co-primary efficacy endpoints are investigator-assessed PFS and OS; key secondary endpoints include independent review facility-assessed PFS and DoR. Safety, pharmacokinetic, biomarker and immunogenicity analyses will be performed. Recruitment is ongoing. Clinical trial information: NCT04543617.

522 Background: Most patients with pancreatic cancer (PC) and biliary tract cancer (BTC) present with advanced disease. In confirmed cases, circulating tumour DNA (ctDNA) may be detected through liquid biopsy in 80-90%. Obtaining a diagnostic biopsy can be technically challenging, require complex invasive procedures and may not be feasible due to comorbidity. Reduction in capacity of aerosol generating diagnostic procedures in many healthcare systems due to COVID19 has highlighted the unmet need for simple, non-invasive diagnostic tools. We piloted the use of ctDNA to support the diagnostic pathway in patients with suspected cancer across 6 tumour types, here we present its use in PC/BTC. Methods: This single centre prospective cohort pilot trial was conducted at the Royal Marsden from June 2020 to August 2021. 16 patients were planned each in the PC and BTC cohorts. Eligibility included radiologically suspicious PC/BTC without histological diagnosis, patients with prior non-diagnostic biopsy and inaccessible tumours. Liquid biopsy for ctDNA was collected for plasma based next generation sequencing, using a custom 59 gene panel of common variants in PC/BTC tumours, including analysis for somatic, copy number and structural variants. Clonal haematopoiesis of indeterminate potential (CHIP) and germline variants were identified and subtracted. A molecular tumour board (MTB) reviewed results for interpretation and clinical context. Primary outcome was the proportion of patients with a ctDNA result consistent with a diagnosis of malignancy following MTB discussion. Results: 32 patients with suspected PC (n= 16) and BTC (n=16) were recruited. Baseline characteristics are shown in table. ctDNA was detected in 69% and 56% of patients with suspected PC and BTC respectively. MTB discussion confirmed all variants detected were consistent with a diagnosis of malignancy. At the time of data cut off, 23 patients had a subsequent biopsy. The sensitivity and specificity of ctDNA as a diagnostic tool was 80% (90% CI 49.3-96.3) and 100% (90% CI 36.8-100) for PC respectively, and 100% (90% CI 60.7-100) and 75% (90% CI 24.9-98.7) for BTC respectively. There were 2 false negatives in the PC cohort subsequently diagnosed with PC, and 1 false positive in the BTC cohort subsequently diagnosed with oesophageal cancer. Conclusions: ctDNA can be used to support a diagnosis of cancer in patients with radiologically suspected PC/BTC. A blood first, tissue second strategy in the diagnosis of PC/BTC could improve diagnostic efficiency, speed, and add resilience to the current diagnostic pathway. Clinical trial information: NCT04566614. [Table: see text]

TPS3620 Background: Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate consisting of an anti-HER2 antibody (trastuzumab) linked to a potent topoisomerase I inhibitor (DXd). T-DXd has been approved to treat HER2-positive metastatic breast cancer (United States, Japan, Europe) and advanced gastric cancer (United States, Japan). It is currently being evaluated in other solid tumor types including colorectal cancer. The phase 2 DESTINY-CRC01 study included patients with RAS wild-type mCRC, with median 4 (range, 2-11) prior lines of therapy. Preliminary results in patients with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) mCRC showed T-DXd treatment (6.4 mg/kg intravenously [IV] every 3 weeks [Q3W]) resulted in a confirmed objective response rate (ORR) of 45.3% (24/53; 95% CI, 31.6%-59.6%) and a median progression-free survival (PFS) of 6.9 months (95% CI, 4.1 months-not evaluable; Siena J Clin Oncol. 2020;38[15]:4000). Activity was also seen in patients treated with prior anti-HER2 therapy. Although 5.4-mg/kg and 6.4-mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer indications, the lower dose has not yet been tested in patients with HER2-overexpressing mCRC. Preliminary data also suggest T-DXd may be active in RAS mutant mCRC, unlike other anti-HER2 therapies. The DESTINY-CRC02 study aims to determine efficacy and safety of T-DXd in patients with HER2-overexpressing, RAS wild-type or mutant mCRC at 5.4-mg/kg and 6.4-mg/kg doses. Methods: DESTINY-CRC02 (NCT04744831) is a multicenter, randomized, double-blind, 2-arm, parallel phase 2 study that will be conducted in 2 stages. Eligible patients (≥18 years; ≥20 years in Japan, Taiwan, and Korea) will have HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) locally advanced, unresectable or metastatic CRC and have previously received chemotherapy, anti-EGFR therapy, anti-VEGF treatment, and/or anti–PD-1/PD-L1 therapy, as clinically indicated. Prior anti-HER2 therapy will be allowed. In stage 1, patients will be randomly assigned 1:1 to receive T-DXd IV Q3W at a dose of 5.4 mg/kg (n = 40; arm 1) or 6.4 mg/kg (n = 40; arm 2). Randomization will be stratified by ECOG PS (0 or 1), HER2 status (IHC 3+ or IHC 2+/ISH+), and RAS status (wild-type or mutant). After stage 1 enrollment is complete, eligible patients in stage 2 (n = 40) will receive T-DXd 5.4 mg/kg until disease progression or other treatment discontinuation criteria are met. The study is actively enrolling and aims to enroll 120 patients across 60 sites. The primary objective is to assess efficacy of T-DXd at the 5.4-mg/kg and 6.4-mg/kg doses, with a primary end point of confirmed ORR by blinded independent central review. Secondary end points include investigator-assessed ORR, PFS, duration of response, disease control rate, clinical benefit rate, overall survival, pharmacokinetics, and safety. Clinical trial information: NCT04744831.

57 Background: Real world data is a valuable research resource but manual data collection is time consuming and labour intensive. As there is no consensus on the prognostic role of TP53 and PIK3CA mutations in mCRC, we assessed the feasibility of using SQL, a programming language, to derive data from routine electronic clinical notes to investigate the prognostic impact of TP53 and PIK3CA mutations in mCRC. Methods: A cohort of patients (pts) diagnosed with metastatic or recurrent colorectal cancer as per ICD-10 classification from January 2015 to December 2017 and managed at the Royal Marsden Hospital were identified using SQL algorithms developed in-house. Baseline demographics, histopathological and molecular characteristics and death dates were derived from the Electronic Patient Record and extracted in a structured format for statistical analysis. Mutational analysis of TP53 and PIK3CA were performed with standard of care KRAS, NRAS and BRAF testing using next generation sequencing. Overall survival (OS) according to TP53 or PIK3CA mutational status was estimated using the Kaplan-Meier method. Uni- and multivariate Cox regression included KRAS, NRAS, BRAF, sidedness and mismatch repair (MMR) status. Association between TP53 or PIK3CA and MMR status was tested by the Chi squared test. Results: A total of 367 mCRC pts were identified; 10 were excluded due to ineligibility or inadequate data availability. Based on a final dataset of 357 pts, 342 and 354 pts had TP53 and PIK3CA results available. The incidence of TP53 mutations was 75% (n = 257/342) and PIK3CA 16% (n = 55/354). Co-mutations with KRAS, NRAS and BRAF were seen (Table). The overall median follow-up was 42.3 and 42.7 months for TP53 and PIK3CA respectively. There was no difference in OS between TP53 mutant (MT) and wild type (WT) pts (22.0 vs. 22.8 months, p = 0.96) and between PIK3CA MT and WT pts (21.7 vs. 22.4 months, p = 0.49). Right sided and BRAF MT tumours were associated with poorer survival than left sided and BRAF WT tumours when all other factors were constant for TP53 (p

262 Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]