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Epstein–Barr virus (EBV) contributes to oncogenesis and immune evasion in nasopharyngeal carcinoma (NPC). At present, an aggregated, higher-level view on the impact of EBV genes toward the immune microenvironment of NPC is lacking. To this end, we have interrogated tumor-derived RNA sequences of 106 treatment-naive NPC patients for 98 EBV transcripts, and captured the presence of 10 different immune cell populations as well as 23 different modes of T-cell evasion. We discovered 3 clusters of EBV genes that each associate with distinct immunophenotypes of NPC. Cluster 1 associated with gene sets related to immune cell recruitment, such as those encoding for chemoattractants and their receptors. Cluster 2 associated with antigen processing and presentation, such as interferon-related genes, whereas cluster 3 associated with presence of M1-like macrophages, absence of CD4+ T cells, and oncogenic pathways, such as the nuclear factor kappa light-chain enhancer of activated B-cell pathway. We discuss these 3 EBV clusters regarding their potential for stratification for T-cell immunity in NPC together with the next steps needed to validate such therapeutic value.

Purpose:Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).Patients and Methods:Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.Results:Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.Conclusions:Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.

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Recent data from several randomized controlled trials (RCTs) have shown that Total Neoadjuvant Therapy (TNT) can improve the treatment outcome of patients with high-risk rectal cancer from Western and East Asian populations. Systemic intensification with chemotherapy administered before (induction) or after (consolidation) neoadjuvant radiotherapy (RT) prior to total mesorectal excision (TME) surgery has been shown to improve disease-free survival (DFS), pathologic complete response (pCR) rate, treatment compliance and/or reduce the risk of disease-related treatment failure for high-risk rectal cancer. In this review we highlighted the key results of RCTs on different TNT approaches conducted in Western and Asian populations, and their impact on clinical practice and research direction. We discussed the salient issues and controversies arising from these studies such as the optimal duration of TNT, factors affecting patient selection and the feasibility of adopting a watch-and-wait approach in complete responders to TNT. There are considerable variations between treatment guidelines from Western and East Asian regions on adopting TNT in the management of high-risk rectal cancer, therefore reflecting regional differences in oncologist's preferences and feasibility in implementing TNT. The review concluded by providing an update on some of the key ongoing RCTs into a risk-adapted approach to incorporating TNT in clinical practice, and also translational research into predictive and prognostic biomarkers of response to TNT for high risk rectal cancer.

RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used.To review routine care RAS testing and results over time.A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018.Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018).Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary.To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS.Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p0.0001), and inferior OS (median 15.1 vs. 36.6 months; p0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively.LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

PURPOSE: Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane). PATIENTS AND METHODS: Postmenopausal women with hormone receptor-positive (HR(+)), human epidermal growth factor receptor 2-negative (HER2(−)), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy. RESULTS: Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response. CONCLUSIONS: Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR(+), HER2(−) ABC.

50 Background: Liver metastatectomy in oligometastatic colorectal cancer (CRC) can result in long-term disease control1. The benefit of resecting LM is unclear, with good survival outcomes from medical therapy (MT) alone and a recent randomised controlled trial failed to demonstrate an overall survival (OS) benefit2. Methods: We examined TRACC (Treatment of Recurrent and Advanced Colorectal Cancer), a multisite registry for metastatic colorectal cancer (mCRC) patients (pts) from September 2002 – July 2021, focusing on the longer-term outcomes for pts with lung only metastatic disease (LOM). Key clinicopathological, treatment and outcome variables were analysed. Survival outcomes were determined by Kaplan-Meier method. Results: Of 3928 pts, 341 (8.7%) had LOM. The median OS was significantly improved for LOM vs. all mCRC pts (44.5 months vs. 24.8 months, p =

BACKGROUND Patients with International Union Against Cancer (UICC) Stage I–II nasopharyngeal carcinoma (NPC) appear to have a relatively favorable prognosis and generally are excluded from trials of combined modality treatment. More recently, plasma/serum cell-free Epstein-Barr virus (EBV) DNA has been shown to be measurable in the majority of NPC patients at the time of diagnosis, and appears to have prognostic significance. However, within Stage I-II disease, in which failure events are infrequent, the prognostic impact of the pretreatment EBV DNA level has not been addressed to our knowledge. This issue has management implications because different therapeutic strategies currently are employed for patients with good-risk and those with poor-risk NPC. METHODS A cohort of 90 patients with UICC Stage I-II NPC (World Health Organization Grade 2/3 histology) had their pretherapy plasma/serum EBV DNA levels determined by a quantitative polymerase chain reaction assay and correlated with the probability of posttherapy failure. All patients received radiation therapy only, except for three patients who also received concurrent chemotherapy. Kaplan–Meier plots of the probability of locoregional failure, distant failure, and cancer-specific survival were compared with reference to clinical stage and EBV DNA levels. RESULTS With a median follow-up time of 45 months, 12 patients and 7 patients, respectively, had developed locoregional and distant failures, including 2 patients with both local and distant failures. Patients with distant failure had significantly higher pretherapy EBV DNA levels than those without failure (a median of 13,219 copies/mL [interquatile-range, 274,635 copies/mL] vs. a median of 423 copies/mL [interquatile-range, 2753 copies/mL]). The probability of distant failure was significantly higher in patients with high (> 4000 copies/mL plasma) compared with low EBV DNA levels (P = 0.0001, log-rank test) and for Stage IIB disease compared with Stage I and Stage IIA disease combined (P = 0.0149, log-rank test), but was not significantly different between patients with Stage II and those with Stage I disease. The risks of locoregional failure were not significantly different between patients with high and those with low EBV DNA levels, and also was not significantly different between clinical substages. Approximately 35% of patients with Stage IIB disease were in the at-risk group for distant failure, as identified by high EBV DNA levels. CONCLUSIONS Within a group of patients with UICC Stage I-II NPC, the pretherapy plasma EBV DNA level was found to identify a poor-risk group with a probability of distant failure similar to that of patients with advanced stage disease. This group of patients may warrant management considerations currently applicable only to cases of Stage III-IV disease. The prognostic significance of designating Stage IIB disease as per the 1997 UICC staging was confirmed, although the pretherapy EBV DNA level appears to be a more powerful prognostic discriminator in patients with early-stage NPC. Cancer 2003;98:288–91. © 2003 American Cancer Society. DOI 10.1002/cncr.11496

697 Background: The CONCUR trial (NCT01584830) showed that the multikinase inhibitor regorafenib (REG) significantly improved overall survival and progression-free survival vsplacebo (PBO) in Asian patients with mCRC who had progressed on approved standard therapies. HRQoL was an exploratory endpoint. Methods: In this international multicenter trial conducted in Asia, patients were randomized 2:1 to receive REG 160 mg (n=136) or PBO (n=68) once daily for the first 3 weeks of each 4-week cycle. Prespecified QoL analyses were conducted on all 204 patients using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol-five dimension questionnaire (EQ-5D). HRQoL outcomes were expressed as time-adjusted area under the curve (AUC) to allow descriptive evaluations of QoL in the REG and PBO groups across the entire treatment period. Individual domains were also compared using descriptive statistics. Results: Overall, changes in HRQoL were similar in the REG and PBO groups. Difference in least-squares (LS) mean time-adjusted AUC of the EORTC QLQ-C30 global health status/QoL (GH) score: −0.40 (95% CI: −3.53 to 2.72); differences in LS mean time-adjusted AUC for EQ-5D index and visual analog scale (VAS) scores: −0.03 (95% CI: −0.08 to 0.01) and −1.18 (95% CI: −4.01 to 1.66), respectively. The PBO group had

5511 Background: The benefit of adjuvant CT in NPC is unclear. Administering CT after full-dose CRT presents challenges in treatment compliance and toxicity. Post-RT EBV DNA predicts poor survival and may be a biomarker of subclinical residual disease. We conducted a biomarker driven RCT using EBV DNA to select high risk NPC patients (pts) for adjuvant CT while sparing low risk pts from unnecessary toxicity. Methods: Biopsy proven NPC, AJCC stage IIB-IVB, detectable EBV DNA at 6-8 wks post-RT, no persistent locoregional disease or distant metastasis, ECOG 0 or 1, adequate organ function. Randomised with stratification for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A (adjuvant cisplatin 40 mg/m2 and gemcitabine 1000mg/m2, both given on D1+8 q3w x 6 cycles) or arm B (clinical follow-up). EBV DNA and PET scan were performed before and 6 months after randomization. Primary endpoint was relapse free survival and secondary endpoints included toxicity of adjuvant CT. With a hazard ratio of 2, 100 pts were required with a power of 0.8 and an alpha at 0.05. This safety analysis was approved by DMSC. Results: From 9/2006 to 12/2011, 514 pts consented for EBV DNA screening, 95 with detectable EBV DNA consented for adjuvant study. After work-up, 74 were eligible for randomization (37 to arm A; 37 to arm B). The two arms were well balanced in baseline characteristics. 80% received prior neoadjuvant and/or concurrent CT. Staging: IIB (36.5%), III (29.7%), IVA (18.9%), IVB (14.8%). Five pts refused adjuvant CT after randomization. Overall 65% and 57% completed 5 and 6 cycles respectively. Mean dose intensity (DI): 84% for cisplatin (22.5 mg/m2/wk, range 0.0-26.7), 92% for gemcitabine (612.8 mg/m2/wk, range 333.3-777.8). Treatment related adverse events above CTC G2 were summarized in Table. Conclusions: Delivery of 6 cycles of adjuvant CT is feasible with acceptable toxicity after full dose RT or CRT. [Table: see text]