Microsatellite-stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI). The MAYA trial used temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesizing that TMZ-induced hypermutation could sensitize tumors to ICI; the primary endpoint was met, showing durable responses with TMZ plus ipilimumab and nivolumab. We perform integrated spatial, transcriptomic, and immune profiling of longitudinal tumor and blood samples from patients treated on the MAYA trial. Post-TMZ increases in tumor mutational burden associate with improved progression-free survival. Spatial profiling demonstrates that clinical benefit is greatest in permissive tumor microenvironments. Responders exhibit enrichment of cytotoxic T cells across tumor and stromal compartments, whereas non-responders display heterogeneous cellular neighborhoods, with fibroblasts in close spatial proximity to T cells, consistent with barriers to immune-mediated clearance. Longitudinal peripheral immune profiling shows that early upregulation of TIGIT and PD-1 following TMZ exposure predicts resistance. Together, these findings indicate that both mutational evolution and spatial immune architecture contribute to immune sensitization in MGMT-silenced MSS CRC. Clinical Trial Identification: NCT03832621.

Scalp cooling is standard-of-care for prevention of chemotherapy-induced alopecia (CIA), with proven safety and efficacy. Limb cryotherapy has shown promise in preventing chemotherapy-induced peripheral neuropathy (CIPN). The safe application of concomitant scalp and limb cryotherapies during chemotherapy is crucial due to concerns about potential interactions, including central hypothermia, yet limited data exist on their safe delivery in this context. Here we report a prospective, single-arm study assessing feasibility, safety, and tolerability of concomitant scalp cooling and limb cryocompression in healthy volunteers, and in cancer patients undergoing chemotherapy. Safety and tolerability of concomitant scalp cooling and limb cryocompression were evaluated in healthy volunteers and then in cancer patients receiving weekly paclitaxel chemotherapy. Limb cryocompression was administered starting at 11 °C, with thermoregulation allowed up to 25 °C to accommodate patient tolerance. Core body temperature changes, adverse events (CTCAE v4.0), and tolerance to cryotherapy were documented. EORTC Quality of Life Questionnaire-CIPN20 scores were evaluated before the start of chemotherapy (QoLpre), after the last cycle of chemotherapy (QoLpost), and 3 months after the last cycle of chemotherapy (QoL3m). Physician grading of CIA was documented using CTCAE v4.0, and results at baseline and at completion of weekly paclitaxel were compared. Concomitant scalp and limb cryocompression at 11 °C was safe and tolerable in healthy volunteers (n = 3). Fifteen patients enrolled in the study and 13 completed the entire treatment, with negligible core body temperature changes (− 0.18 °C ± 0.37). Eight patients completed all 12 cycles of cryocompression at 11 °C while some required thermoregulation (range 14 °C to 18 °C). One patient completed all cryotherapy cycles at 25 °C and another withdrew due to intolerance to 25 °C. There were no occurrences of ≥ Grade 2 neuropathy. QoL was preserved and scores remained stable at QoL3m (18 (18–21); median (IQR)) compared to QoLpre (18 (18–19)). Patients who underwent cryocompression at lower temperatures showed better preservation of QoL scores (QoL3m 18 (18–20)) than the others (QoL3m 26 (22–31)). 11/13 patients (85

Introduction: Atezolizumab plus bevacizumab is a commonly used first-line regimen for advanced hepatocellular carcinoma (HCC) treatment owing to its superior outcomes compared to sorafenib. However, optimal subsequent treatment options for patients with HCC who progressed on first-line atezolizumab plus bevacizumab remain unclear. Methods: This multinational, multi-institutional, retrospective study included patients with HCC from 22 centers in five Asia-Pacific countries who were treated with first-line atezolizumab plus bevacizumab, which was discontinued for any reason. The endpoints included progression-free survival (PFS) and overall survival (OS) according to patient characteristics and second-line regimens. Results: Between June 2016 and May 2023, 1,141 patients were treated with first-line atezolizumab plus bevacizumab, of whom 629 (55.1%) received subsequent treatment. Sorafenib and lenvatinib were the most commonly administered second-line regimens (53.9% and 25.6%, respectively). Overall, the median PFS and OS were 2.9 and 8.0 months, respectively. Lenvatinib had longer PFS (4.0 vs. 2.3 months) and OS (8.0 vs. 6.3 months) than sorafenib. Patients treated with tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) (n = 50, 8.3%) showed PFS and OS of 5.4 and 12.6 months, respectively. Lower tumor burden and lenvatinib or TKI plus ICI use were associated with longer second-line PFS. Preserved liver function was associated with improved OS. Conclusions: In patients with HCC who progressed on first-line atezolizumab plus bevacizumab, sorafenib and lenvatinib were the most commonly used second-line regimens in Asia-Pacific countries, with lenvatinib resulting in longer OS than sorafenib. The second-line TKI plus ICI combination exhibited promising efficacy, suggesting the potential role of continuing ICIs beyond disease progression.

Knudson’s “two-hit” paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson’s paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2’s tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson’s two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

39 Background: Multiple studies of TNT for LARC have shown improved pathological complete response (pCR) rate and disease-free survival (DFS). However, real-world data in Asia is limited. Methods: Patients (pts) diagnosed with LARC at National University Cancer Institute, Singapore were discussed at a multidisciplinary tumor board. Patients were eligible for TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin (CRM) and adequate organ function. TNT protocol was systemic chemotherapy with 5-6 cycles of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or 3-4 cycles of XELOX (capecitabine, oxaliplatin) followed by short- or long-course chemoradiation (CRT), then 3 cycles of mFOLFOX6 or 2 cycles of XELOX. Clinical outcomes included rates of clinical complete response (cCR), pCR, surgery type, R0 resection and DFS. Baseline pt demographics, laboratory results and tumor characteristics were analyzed against these outcomes. Results: 173/205 pts who were diagnosed with rectal cancer between February 2020 and November 2022 had LARC and 47 received TNT. Median age was 65 (range: 33-79), 68.1% male, 78.7% were Chinese, 19.2% had cT4 tumors, 87.2% node positive and 80.9% had CRM involvement. Median tumor distance from anal verge was 6cm (range: 1-15cm) on colonoscopy and 5cm (range: 2-12cm) on magnetic resonance imaging. 95.7% received XELOX, 87.0% had long-course CRT and 83.0% completed all cycles of systemic chemotherapy and CRT. 44.7% had dose reduction of systemic therapy and 4.3% required emergent surgery due to local complications during TNT. After TNT completion, 7 pts did not pursue surgery – 3 achieved cCR (6.4%) and adopted a watch-and-wait approach, 2 had disease progression (PD), and 2 declined. Of those who underwent surgery, 75.0% had sphincter-preserving surgery and 85.0% achieved R0 resection. 2.1% (n =1) achieved pCR. Rates of tumour regression grade (TRG) 0, 1, 2, 3 were 7.5%, 15.0%, 67.5% and 10.0%, respectively. After a median follow up of 21.7 months (range: 9.3 – 41.6 months), 21.3% (n = 10) had disease recurrence and 14.9% (n=7; 5 from PD, 1 from surgery-related complication, 1 unrelated to treatment) passed away. 1-year DFS rate was 88.7% (95% CI 75.0% - 95.2%). Conclusions: This is the first Asian study reporting real-world data of TNT for LARC since its wide-scale adoption. pCR rates appear lower than reported studies. Understanding the limitation of retrospective studies, further analysis is ongoing to determine if factors other than sequence of modality can contribute to the observed findings.

Abstract Background: Adoptive cellular therapy (ACT) has been transformative in the treatment of hematological malignancies. Limitations of ACTs include difficulty identifying suitable tumor antigens for solid tumors, the ability to target only one antigen per construct which commonly results in secondary resistance due to antigen escape, and largely autologous approaches which are challenging in heavily pre-treated patients with poor marrow function and those with rapidly progressive disease who may not receive their personalised cellular products in time. This is a phase I study evaluating a novel off-the-shelf allogenic mRNA-electroporated NKG2D ligand-targeting CAR-grafted γδ T cell therapy. NKG2DLs are a group of 8 types of stress-induced cancer antigens which are preferentially and widely expressed on tumor cells from diverse tissue origins but are not typically present on normal tissue. NKG2DL-targeting γδ T cells will be manufactured from peripheral blood mononuclear cells isolated from healthy donors enrolled on the donor protocol of the ANGELICA trial. ANGELICA is a phase I study evaluating the safety, tolerability and recommended phase 2 dose (RP2D) of NKG2DL-targeting CAR-grafted γδ T cells in patients with treatment refractory tumors. Methods: Patients will be enrolled in a 3+3 design. Dose escalation will be performed at 3 dose levels: 1x108, 3x108 and 1x109 per infusion (adjusted for body weight). Lymphodepletion with fludarabine 25mg/m2/day and cyclophosphamide 250mg/m2/day will given for 3 days and completed at least 2 days prior to the first cycle of treatment. Patients will receive 4 doses of weekly infusions for the first cycle, with up to 5 subsequent infusions every 2 months as maintenance. Patients will receive intravenous zoledronic acid 1mg prior to each cellular infusion and subcutaneous IL-2 1x106 IU/m2 within 2 hours of each cellular infusion as pre-clinical data demonstrated cancer cell sensitisation and prolonged γδ T cell survival with these adjuncts. Dose-limiting toxicities will be assessed over the first 8 weeks. Adverse events, response rates (RECIST v1.1), survival outcomes and immunomonitoring (immune cell phenotyping and serum cytokine analysis) will be assessed. The trial is currently enrolling healthy donors; enrolment of patients at the first dose level will begin in February 2024. NCT05302037 TABLE 1: NAND Dose Level and Schedule Dose Level Dose per infusion Infusion schedule Number of patients 1 Weight 65kg and above: 1x108.Weight less than 65kg: 1.5x106. Cycle 1: weekly x 4 infusions. Maintenance phase: 2-monthly x 5 infusions. 3-6 2 Weight 65kg and above: 3x108.Weight less than 65kg: 4.6x106. 3-6 3 Weight 65kg and above: 1x109.Weight less than 65kg: 1.5x107. 3-6 Citation Format: Joan Choo, Wee Kiat Tan, Lucas Luk, Jieming Zeng, Teck Guan Soh, Sou Yen Soon, Jedidah Lieow, Calista Wong, Mei Yan Pang, Sudipto Bari, Michelle Poon, Liang Piu Koh, Wee Joo Chng, Anand Jeyasekharan, Lip Kun Tan, Esther Chan, Raghav Sundar. A phase I trial to evaluate allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells in subjects with advanced solid tumors or hematological malignancies (the ANGELICA Trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT160.

Purpose Scalp cooling therapy (SCT) improves chemotherapy induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy. Methods The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane based chemotherapy. Only patients with Grade (G) 0–1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 minutes prior to and continuing up to 90 minutes after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0–2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy. Results 83 participants were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 (indicating that procedure was comfortable) and above upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3-weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation. Conclusion SCT is well tolerated in an Asian predominant population. Among women with breast or gynaecological cancers in Singapore receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls.

6649 Background: The risk of recurrence for colorectal cancer (CRC) is low after 5 years (<1.5% per year) hence, surveillance visits, CEA blood tests and annual CT scans are not recommended beyond this period (NCCN guidelines). Importantly, right-siting survivorship care to the community allows primary care providers (PCP) to focus on preventive health beyond cancer. The National University Cancer Institute, Singapore, a tertiary, academic cancer center developed a program to transition CRC survivorship care to the community after 5-years of active surveillance. Patients (Pts) are discharged to the community with a survivorship care plan and followed-up via phone calls. We hypothesize that by transitioning CRC survivors to the community, we can optimize healthcare resources by reducing specialist visits and tests at the cancer center without compromising outcomes. Methods: From July 2018, CRC pts beyond 5-years from diagnosis with no evidence of cancer recurrence were eligible for transition. Pts were followed prospectively to determine date of cancer recurrence, issues preventing transition to the community and a phone survey on pt satisfaction was conducted for those who transitioned to primary care. Data on healthcare utilization amongst pts who transitioned vs. pts who remained in tertiary care was collected. Data cutoff was June 2022. Statistical analysis was performed with IBM SPSS Statistics (v28.0). Results: Between July 2018 - June 2022, there were 791 CRC pts who were eligible for transition, of which 534 pts (67.5%) had no clinical issues preventing transition and included in this analysis. 54.3% (N= 290) were males and stage distribution of cancers were 14.2%, 34.0%, 47.1% and 4.7% for stages I, II, III and IV, respectively. The mean number of years since diagnosis was 6.88 (range: 5-16 years; SD 2.25). 380 pts (71.2%) were transitioned to the community. There was consistently higher utilization of healthcare resources in the group not transitioned vs. transitioned: mean number of consults (2.86 vs 1.02; p<0.001); CEA (1.23 vs 0.31; p<0.001); CT scans (0.08 vs 0.05; p=0.221) and colonoscopies (0.25 vs 0.16; p=0.031). Mean healthcare expenditure (mean gross bill per year) was consistently higher in pts across all categories for the group not transitioned vs. transitioned: consults ($158 vs $56; p<0.001); CT scans ($60 vs $39; p=0.273); CEA ($26 vs $7; p<0.001) and colonoscopies ($208 vs $126; p=0.018). Importantly, recurrence rates were low with no difference in both groups (0.8% vs 1.3%; p=0.629). 82% of CRC pts were satisfied or very satisfied with follow-up care provided by their PCPs on a subsequent survey. Conclusions: We have demonstrated value-driven survivorship care by right-siting CRC survivors into the community. Healthcare resources were optimized with reduction in specialist visits and tests which lead to lower costs while recurrence rates remain low. Pt satisfaction in the community was also high.

1099 Background: Fluoropyrimidines are commonly used in the treatment of patients (pts) with metastatic breast cancers (MBC). FTD/TPI is an oral drug combination of trifluridine with tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus allowing for increased exposure to active agent, and has showed activity in pts with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in MBC pts with (Cohort A) or without (Cohort B) prior exposure to fluoropyridines in a single arm phase II study. Methods: Pts were treated with FTD/TPI, and enrolled first into a lead-in dose confirmation phase, followed by two parallel cohorts based on prior exposure to fluoropyrimidines. Primary objectives for each cohort included determination of progression-free survivals (PFS), and secondary objectives included determination of objective response rates (ORR), safety and tolerability. Results: A total of 74 pts were recruited (42 for Cohort A, 32 for Cohort B), of whom 4 belonged to lead-in phase. Dosing was confirmed at FTD/TPI 35mg/m 2 days 1-5 and 8-12 of 4-weekly cycles based on lead-in phase with no dose-limiting toxicities observed, and recruitment then proceeded in 2 parallel cohorts. All pts were evaluable for toxicity and survival analyses, and 72 were evaluable for ORR. Median age at enrolment was 62 years (range 32-85), with median of 4 (range 0-14) prior lines therapy in the metastatic setting, and 47% had de novo metastatic disease. Median PFS was 5.7 months (95% CI 3.8 to 8.3) and 9.4 months (95% CI 5.5 to 14.0) respectively in Cohorts A and B. Similar response rates were observed regardless of prior exposure to fluoropyrimidine, with ORR of 19.5% (95% CI 8.8 to 34.9) and 16.1% (95% CI 5.5 to 33.7) in Cohorts A and B, with 6-month clinical benefit rates of 56.1% (95% CI 39.7 to 71.5) and 61.3% (95% CI 42.2 to 78.2) respectively. Safety profile was consistent with known toxicities of FTD/TPI, with most common treatment-related adverse events of neutropenia, fatigue, nausea and anorexia. 64% of pts required dose modifications during study treatment, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation from 4- to 5-weekly cycles. Only 1 pt required discontinuation due to toxicity from therapy. Conclusions: FTD/TPI showed promising anti-tumor activity with meaningful clinical benefit even among pts with prior exposure to fluoropyrimidines, and has a reasonable toxicity profile with appropriate dose modification. An oral chemotherapy option with good disease control provides an attractive treatment alternative to pts with MBC where quality of life is paramount, warranting further investigation in randomised studies. Clinical trial information: NCT04280536 .

Background We evaluated the relevance of PD-1 + CD8 + T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME). Methods Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the “3G” chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs. Results In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B + ] ( r = 0.714, p < 0.001) and proliferative [Ki-67 + ] ( r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1 high compared to CD8PD-1 low tumors. Conclusion This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1 + CD8 + T-cells being associated with improved OS. CD8PD-1 high tumors have distinct features of an immunologically active, T-cell inflamed TME.

Immune checkpoint inhibitors (ICIs) has changed the landscape for advanced hepatocellular carcinoma (aHCC). Here, we sought to explore survival outcomes of ICI versus non-ICI regimens across viral and non-viral aHCC aetiologies.

3584 Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.

165 Background: The addition of intraperitoneal (IP) paclitaxel (PTX) to systemic chemotherapy comprising taxane/fluoropyrimidine doublet has shown promising results for patients with gastric cancer (GC) and peritoneal metastases (PM). However, this has not been studied in combination with platinum/fluoropyrimidine doublet which is the current standard-of-care for metastatic GC. We conducted a prospective phase 2 trial of IP PTX with capecitabine and oxaliplatin (XELOX) in patients with GCPM. Methods: The trial enrolled 44 patients with GCPM who received treatment comprising IP PTX (40mg/m2 on day 1,8), PO capecitabine (1000mg/m2 twice daily from day 1-14) and IV oxaliplatin (100mg/m2 on day 1) in 21-day cycles. Patients with synchronous GCPM were eligible for conversion surgery comprising radical gastrectomy if they had good response after chemotherapy, negative cytology on 2 consecutive peritoneal fluid assessments, no extraperitoneal metastasis and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were also compared with a retrospective cohort of 39 patients with GCPM who received identical systemic chemotherapy (SC) comprising platinum/fluoropyrimidine agents alone. Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (HR 0.44; 95% CI, 0.26-0.74; P=0.002). The 1-year OS was 67.8% in the IP group and 32.3% in the SC group (Logrank p<0.001). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI, 0.25-0.66; P<0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p=0.021) and had better baseline performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p=0.007) compared to the IP cohort. In the IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95%CI 13.1 – 35.3) months and 1-year OS of 84.6%. Wound-related complications requiring the port to be explanted or re-sited occurred in 9% (4/44) of patients. Conclusions: IP PTX with XELOX is a promising treatment option for GCPM patients. For patients with good response, conversion surgery was feasible with favourable outcomes. Clinical trial information: NCT01739894. [Table: see text]

Supplementary Figure from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Breast cancers are heterogeneous with variable clinical courses and treatment responses. We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents. Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment. Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2−/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029). Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy. ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Abstract Background Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non‐small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real‐world setting. Method Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT‐durvalumab. Primary endpoints were progression‐free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT‐durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. Results A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT‐durvalumab. Median PFS was 17.5 months for CCRT‐durvalumab and 8.9 months for CCRT‐alone (HR 0.47, p = 0.038). Median OS was not‐reached for CCRT‐durvalumab and 22.3 months for CCRT‐alone (HR 0.35, p = 0.024). Both EGFR‐positive and wild‐type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT‐alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p‐value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil‐to‐lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet‐lymphocyte‐ratio ≥ 180 was associated with a lower risk of pneumonitis. Conclusion In this real‐world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

570 Background: Gemcitabine-based chemotherapy is an approved therapy for treatment-naïve metastatic pancreatic ductal adenocarcinoma (PDAC). Inherent resistance to gemcitabine inevitably leads to cancer progression and shorter survival. It has been demonstrated that bacteria are a component of the PDAC tumor microenvironment and may play a critical role in mediating resistance to chemotherapy. Hence, the coadministration of an antibiotic to chemotherapy may potentiate antitumour drug responses. We conducted a pilot study to assess the efficacy and safety of ciprofloxacin plus gemcitabine-based chemotherapy in patients with treatment naïve metastatic PDAC. We also aimed to study gut microbiome changes during treatment with ciprofloxacin. Methods: This was a single arm study conducted at the National University Cancer Institute, Singapore. Patients (pts) with histologically confirmed metastatic PDAC were treated with nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks, in combination with oral ciprofloxacin 500 mg twice daily. Treatment was continued until disease progression or intolerable toxicity. DNA extraction, 16S rRNA amplification and sequencing for bacteria were performed on pre- and post-treatment stool samples. Primary endpoint of this study was response rate and safety of the treatment combination. Secondary endpoints included progression free survival (PFS), overall survival (OS) and microbiome changes after treatment with ciprofloxacin. Results: From Mar 2019 – Feb 2021, 8 pts were recruited. Median age was 71 years old. Best response was stable disease in 5 (62.5%) pts and 3 pts had progressive disease (PD). Median PFS and OS were 4.3 and 15.4 months, respectively. 2 pts developed grade 4 neutropenia and 1 pt had grade 3 febrile neutropenia. Rash was common with 50% of pts developed grade 1/2 rash. No additional toxicities from ciprofloxacin were observed. Preliminary stool analysis showed significant differences in individual bacterial strains across all timepoints in the PD vs. SD groups. There was also an increased abundance in gammaproteobacteria resistant to ciprofloxacin treatment in pts with PD. Conclusions: Gemcitabine-based chemotherapy plus ciprofloxacin demonstrated clinical activity and acceptable safety profile in PDAC. Our study also highlighted that gut microbiome may play a critical role in mediating resistance to chemotherapy. Clinical trial information: NCT04523987.

Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials. Methods: This multi-centre study analysed retrospective and prospective data from 456 patients treated with CDK4/6i between January 2015 and December 2020. We examined patient characteristics, variation in prescribing practices, efficacy and toxicity outcomes. Results: In all, 456 patients were included in this study. The median age was 59 (range: 24–92). In total, 85 (19%) were ⩾70 years old. In all, 122 (27%) and 119 (26%) of patients were treated in the first-line and second-line settings, respectively. In total, 25 (5%), 31 (7%) and 145 (32%) of patients had brain, peritoneum and liver metastasis, respectively, at the time of CDK4/6i initiation. On univariate analysis, heavily pre-treated patients and those with distant metastases, involving the liver, brain or peritoneum, had significantly shorter progression-free survival (PFS) and 24-month overall survival (OS). Elderly patients (⩾70) had a shorter PFS; OS results were not mature. Majority of patients ( n = 362, 80%) initiated treatment with the United States FDA-approved starting dose of CDK4/6i. In all, 330 (72%) had at least one DD and 217 (48%) patients required at least one DR, but these dose modifications were not associated with poorer survival outcomes. Patients age ⩾70 were more likely to require dose modifications leading to a lower treatment dose. The most common reason for DD/DR was neutropenia (60%) and the incidence of febrile neutropenia was only 2%. Conclusions: Our study indicates CDK4/6i is effective and safe. Age ⩾ 70, distant metastases to liver, peritoneal or brain were negative prognostic factors. Age ⩾ 70 was associated with significantly increased requirement for dose modification; however, this did not impact survival outcomes. These findings provide reassurance that survival outcomes are not adversely affected in elderly patients when DD/DR is indicated.

Background: The approved doses of the single agent nivolumab – an anti-programmed cell death protein 1 (PD-1) monoclonal antibody – for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. Methods: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. Results: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05–1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25–1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48–6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. Conclusion: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.