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Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium

Financial toxicity in patients with newly diagnosed hepatocellular carcinoma.

538 Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths and has been associated with significant patient (pt) financial liability, however no study has yet examined pt-reported measures of financial toxicity (FT) in this population. We sought to assess pt-reported FT in newly diagnosed HCC and to identify pt-, disease-, and treatment-related factors associated with FT. Methods: Pts with HCC were recruited prior to treatment initiation during their initial visit at a multidisciplinary liver cancer clinic at a tertiary care center between January 2023-May 2024. The Comprehensive Score for Financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT), a validated survey for assessing financial distress in pts with cancer (range, 0-44; lower scores reflect worse financial wellness), was completed by participants during their initial visit. Sociodemographic (age, sex, race, ethnicity, primary language, insurance status, employment status, marital status, highest education completed, household income, living arrangement, home zip code), clinical (Barcelona Clinic Liver Cancer stage, performance status, age-adjusted Charlson comorbidity index, albumin-bilirubin score, presence and etiology of chronic liver disease, Child-Pugh grade, MELD-Na score), and planned treatment (surgery, liver-directed therapy, systemic therapy, clinical trial enrollment) characteristics were evaluated by questionnaires or medical record review. The EORTC QLQ-HCC18 was used to assess pt-reported quality of life (QOL). Area Deprivation Indices were calculated using pts’ home zip codes. Mean COST-FACIT scores were compared using two-sided t test for binary variables and one-way ANOVA for non-binary variables. Results: Among 47 pts enrolled, 35 (74%) completed the COST-FACIT survey. Younger age (<65 vs ≥65 yrs; mean, 20.3 vs 27.8; p=0.05), non-English primary language (non-English vs English; mean, 16.2 vs 26.7; p=0.04), less completed education (high school or earlier vs college or beyond; mean, 23.3 vs 32.0; p=0.02), and worse self-reported QOL (EORTC QLQ-HCC18 score ≥cohort median vs <cohort median; mean, 21.4 vs 29.2; p=0.02) were significantly associated with worse FT. Although not statistically significant, Hispanic ethnicity (Hispanic vs not Hispanic; mean, 16.1 vs 26.4; p=0.07), lack of employment (not employed vs retired vs employed; mean, 15.5 vs 29.4 vs 24.3; p=0.07), and no plan for liver-directed therapy (no vs yes; mean, 17.9 vs 26.7; p=0.07) trended towards worse pt-reported FT. Conclusions: Among pts with newly diagnosed HCC, significantly higher pt-reported FT is associated with younger age, non-English primary language, less completed education, and worse QOL. Efforts are underway to longitudinally follow our study cohort to assess the course of self-reported FT over 1-year follow-up as well as its associations with treatment response and survival.

Disparities in organ preservation rate for high-risk stage I rectal cancer.

37 Background: Guidelines for the treatment of high-risk stage I rectal cancer is a curative oncologic resection, while recommendations for stage II/III rectal cancer include neoadjuvant therapy with the option for organ preservation. The paradoxical nature of treating less advanced stage cancer with more morbid surgery calls into question the use of organ preservation strategies (OP) for less advanced disease. While sphincter preservation is appealing, benefits from OP require commitment to preoperative therapy, which may require more significant time and financial commitments than a single-stage curative treatment. This study aims to evaluate disparities in social determinants of health regarding receipt of OP compared to major oncologic resection for high-risk stage I rectal cancer. Methods: The National Cancer Database was queried to analyze all patients with high-risk stage 1 rectal cancer between 2004-2021. High-risk stage 1 disease was defined as either T2 or T1 tumors with lymphovascular invasion, or grade 3 or 4 differentiation. Covariates in patients who underwent OP, defined as chemoradiation therapy without oncologic resection or local excision, were compared to those who underwent major oncologic resection. Additional variables included age, sex, race, great circle distance, insurance status, education, facility type, income, rurality, and comorbidity index. Univariate and multivariate analyses were utilized to compare association of covariates to OP. Results: Of the 63,762 patients included, 9,261 (14.5%) underwent OP. Increased rates of OP were seen with increasing age (OR 1.029, p<0.0001), female sex (OR 1.147, p<0.0001), higher education level (OR 1.179, p=0.0034), rurality (OR 1.273, p=0.0003) and lower income (OR 0.757 for income >74K, p <0.0001). Interestingly, OP was more frequently utilized at community cancer centers in comparison to comprehensive cancer centers (OR 0.78, p<0.0001) and academic centers (OR 0.842, p=0.0021). Race, insurance status, distance to treatment, and comorbidity index were not statistically significant predictors of OP. Of note, those who underwent OP had a considerable delay in time to first treatment, with median time to treatment of 36 days in comparison to 13 days for oncologic resection. Conclusions: Socioeconomic and demographic variables are associated with receipt of OP. While plausible that a treatment strategy that requires frequent office visits, travel expenses, and time off from work may preclude OP, lower income and rurality had increased odds of OP. Future aims should be directed to identifying root causes of disparities in treatment and their clinical consequences.

Phase II preoperative pembrolizumab for MSI high or MSS/PD-L1 gastric cancer followed by surgery and adjuvant therapy with pembrolizumab (NCT03257163): Results of a multicenter study.

441 Background: Data suggest that patients with tumors with microsatellite instability (MSI-H), EBV expression, or positive PD-L1 expression can benefit from immunotherapy. This trial evaluated PD-1 immunotherapy in this subset of patients with operable gastric cancer. Methods: We present results of a phase 2 multi-institutional clinical trial (NCT03257163). Patients with cT2-T4, N0-N3, M0 gastric adenocarcinoma with MSI-H, PDL1 CPS > 1%, or EBV+ were included. Patients received 2 cycles preop pembrolizumab 200 mg IV q3 weeks followed by surgery. Pembrolizumab was given for 16 additional cycles postoperatively, concurrently with adjuvant chemoradiation (45 Gy) and 5 cycles of capecitabine (825 mg/m2 days 1-14 during cycles 3, 6 and 7; 625 mg/m2 BID days 1-14 during cycles 4 and 5 with radiation). Patients were defined as evaluable if they received > one cycle of postop pembrolizumab. Primary endpoint is DFS, powered to detect 3-yr DFS of 70% with 89% power. Results: All enrolled patients received two cycles of pembrolizumab preoperatively (n=45). Eight patients did not undergo surgery (1 due to frailty, 2 with distant progression on preoperative imaging, 2 with peritoneal disease on surgical exploration and 3 with locally advanced, unresectable tumors). Six patients did not receive adjuvant therapy (2 due to surgical complications, 2 for failure to thrive, 1 refusal and 1 pending adjuvant therapy). 31 patients received adjuvant therapy and are included in the predetermined, evaluable analytic cohort. These 31 patients had a median age of 67 years (range 44 – 85) with 22.6% Hispanic, 29.0% Asian, 25.8% Black and 25.8% White. Median follow-up was 31.1 months (range 3.45-63.8). In these patients, 14 (45.2%) had MSI-H, 2 (6.5%) EBV+, and 29 (93.5%) had PDL1 expression >1% tumors. Most tumors were advanced stage with 81% ≥ cT3 and 58% cN+. In the 31 evaluable patients, the 3-year DFS was 79.4%; 3-year OS was 78.9%. For MSI-H patients, 3-year DFS was 81.8%. For patients with MSS/PD-L1+ tumors, 3-year DFS was 77.8%. For the 45-patient cohort, 3-year DFS was 70%; 3-year OS was 65%. Three patients had pCR, two with MSI-H tumors and one with PD-L1 CPS of 4%. Downstaging occurred in 62.2% of patients, and 40% of surgical specimens had pT0/T1 tumors consistent with significant pathologic responses. Conclusions: A biomarker-driven preoperative treatment strategy for MSI-H, EBV+, and MSS/PDL1+ operable gastric adenocarcinoma patients is promising and warrants additional evaluation. This treatment strategy is novel and effective, and it incorporates immune checkpoint immunotherapy, low dose chemotherapy, and radiation thus avoiding more intensive combination chemotherapy regimens for patients with these biomarkers. Clinical trial information: NCT03257163 .

Assessment of pathologic response in the colorectal cancer cohort of the IMHOTEP phase II trial of neoadjuvant pembrolizumab in dMMR/MSI tumors.

241 Background: Neoadjuvant treatment with immune check point inhibitors has shown promising results in localized deficient mismatch repair/microsatellite instability (dMMR/MSI) colorectal cancer (CRC), notably in terms of pathologic response. However, pathologic response has rarely been precisely assessed on both primary tumor and its corresponding lymph nodes (LN) as an end-point. We performed this analysis on the CRC samples selected from the IMHOTEP trial, a multicenter, single-arm study evaluating peri-operative Pembrolizumab in 4 different cohorts of patients with localized resectable dMMR/MSI tumors. Methods: We analyzed pathologic response on the 56 surgical specimens available from the CRC cohort. Pathologic response was assessed on primary tumor according to the percentage of Residual Viable Tumor (RVT) score, encompassing 4 groups : 0% = pathologic Complete Response (pCR) ; ≤10% = Major Pathologic Response (MPR) ; >10% < 50% = partial Pathologic Response (pPR) ; > 50% = lack of response (noPR). Pathologic response was assessed on lymph node (LN) according to 4 groups : negative LN without sign of sterilization (yN0 reg-), negative LN with sterilization (yN0 reg+) ; metastatic LN without tumor regression (yN+ reg-) ; metastatic LN with tumor regression (yN+ reg+).The type of regression, including colloid, fibrotic and necrotic features was reported, as well as the presence of tertiary lymphoid structures (TLS). pCR and MPR corresponded to pathologic responder patients and pPR and noPR to pathologic non responder patients. Results: In thisCRC cohort pCR, MPR, pPR and noPR were observed in n= 33 (58.9%), 7 (12.5%), 5 (8.9%) and 11 (19.6 %) cases and yN0 reg-, yN0 reg+, yN+ reg-, yN+ reg+ in 41 (73.2%) , 7 (12.5%), 7 (12.5%), and 1 (1.8 % ) cases. There was a significant association between pathologic responders (pCR + MPR) and negative LN status encompassing sterilized LN (p=0.04). Pathologic responders were more frequently associated with classical (Lieberkuhnian) adenocarcinoma than with other CRC special subtypes (mucinous, signet ring-cell, poorly cohesive subtypes)(p<0.01). Colloid response was the most frequent pattern of regression, observed in 42 (75%) cases, and predominant (>80% of pathologic response areas) in 14 (25%) cases. TLS were seen in 46 (82%) cases, without any significant association with the RVT score. However TLS were observed in all CRC cases with MPR. Conclusions: These preliminary results show pembrolizumab efficacy as a neoadjuvant monotherapy in terms of pathologic response on both primary CRC and corresponding LN, highlighting the need for a new and more accurate pathologic score. It also illustrates the potential impact of the histological subtypes. Complementary data will be available after updated pathologic reviewing of additional specimens from CRC patients and will also be correlated with outcome. Clinical trial information: NCT04795661 .

Biopharma dealmaking in 2024

Exploring health related quality of life for women with breast cancer in Ireland and Québec, Canada throughout the COVID-19 pandemic

Abstract The long-term consequences from the COVID-19 pandemic on breast cancer (BC) is highly unknown, however persisting unmet needs and psychosocial difficulties are likely. The objectives of this study were to evaluate the change in health-related quality of life (HR-QoL) from the pandemic to post-pandemic for women living with a diagnosis of BC and to assess the association between COVID-19 stressor impact and HR-QoL in Ireland and Québec, Canada. Women with a diagnosis of BC were initially enrolled in the cohort study. HR-QoL was assessed during the pandemic (2020–2021) and post-pandemic periods (2022). COVID-19 stressor impact was computed post-pandemic, and change in HR-QoL during and post-pandemic was compared between Ireland and Québec using independent t-tests. Multivariable analysis of covariance (ANCOVA) was used to evaluate the association between COVID-19 stressor impact and changes in HR-QoL, and compare it between Ireland and Québec. 405 participants were included from both settings (Ireland n = 267; Québec n = 138). The average HR-QoL improved from the COVID-19 pandemic to post-pandemic, and there were no differences between Ireland and Québec. Women with high COVID-19 stressor impact (18.9% of participants) had a significantly smaller improvement in their overall HR-QoL compared to those with low COVID-19 stressor impact, and this was evident in Ireland (p < 0.004) and Québec (p < 0.0001) but there were no significant differences between Ireland and Québec (interaction p-value > 0.05). Overall, HR-QoL for women with BC improved from pandemic to post-pandemic period. However, similarly in both settings, women who experienced higher levels of COVID-19-related stress had a slower recovery in HR-QoL. These results can guide decisions about health services and policies to adequately address the on-going effect of the pandemic and also prepare for future health crises.

Targeting the mitotic kinase NEK2 enhances CDK4/6 inhibitor efficacy by potentiating genome instability

Efficacy and safety of durvalumab plus tremelimumab for unresectable hepatocellular carcinoma in Thailand: A real-world multicenter observational study.

539 Background: Durvalumab plus tremelimumab (Durva/Treme) andatezolizumab plus bevacizumab are preferable first-line therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the efficacy and safety of Durva/Treme in real world setting. Methods: Fifty patients with uHCC who enrolled in the expanded access program (EAP) for Durva/Treme as the first-line treatment from 12 centers in Thailand were included. Analysis was assessed for objective response rate (ORR), survival, and adverse events. We also compared data with the HIMALAYA study. Results: Median follow-up time was 9.8 months. There were 24 patients alive and 26 patients deceased. The median age was 62 years. Majority of the patients were male (80%). Hepatitis B, C and non-viral cause were identified in 44%, 30%, and 26%, respectively. Ninety-two percent of patients had Child-Pugh A, while 8% had Child-Pugh B(7). Macrovascular invasion was found in 24% of cases. The full data on efficacy and safety were summarized in table below. Conclusions: To date,this is the largest real-world data of Durva/Treme in the first-line treatment of uHCC. Our study demonstrated that Durva/Treme was effective but had lower ORR and higher liver toxicities than what reported in the HIMALAYA study. EAP (N=50) HIMALAYA (N=393) Response by RECIST1.1, n (%) CR PR SD PD Not evaluable 2(4)4(8)24(48)18(36)2(4) 12(3.1)67(17)157(39.9)157(39.9) - ORR (%) 12 20.1 DCR (%) 60 60.1 mPFS (range), mo 5.36(0.2-12.5) 3.78(3.7-5.3) mOS (range), mo NA 16.4 (14.2-19.6) Adverse events, n (%) A ny grade G rade > 3 A ny grade G rade > 3 Any AE Diarrhea Rash AST elevation ALT elevation Increase bilirubin Hypothyroidism Myocarditis Myositis 37(74) 3(6) 12(24) 23(46) 21(42) 8(16) 7(14) 1(2) 1(2) 12(24) 1(2) 0 6(12) 7(14) 4(8) 01(2) 1(2) 378(97.4)103(26.5) 87(22.4) 48(12.4) 36(9.3) 20(5.2) 47(12.1) -- 196(50.5)17(4.4) 6(1.5) 20(5.2) 10(2.6) 3(0.8) 02(0.5) 3(0.8)

Tumor vascularity as a predictor of FGFR inhibitor response in FGFR2-fused intrahepatic cholangiocarcinoma.

638 Background: Fibroblast growth factor receptor 2 (FGFR2) fusion is a well-established mutation in intrahepatic cholangiocarcinoma (iCCA), accounting for approximately 10% of cases. Current treatments, including pemigatinib, infigratinib, and futibatinib, have shown promising results with response rates of less than 40%. Most patients experience progression within 6-8 months, and reliable biomarkers to predict treatment response are still lacking. This study aimed to assess the clinical outcomes of FGFR inhibitors in patients (pts) with FGFR2-fused iCCA, while investigating tumor vascularity as a potential predictor of treatment efficacy. Methods: We retrospectively analyzed data from 134 pts treated at MD Anderson Cancer Center between 2009 and 2024, focusing on 73 pts with comprehensive clinical data. The cohort included pts treated with futibatinib (n=16), infigratinib (n=16), pemigatinib (n=36), and derazantinib (n=5). Tumor vascularity was assessed via Hounsfield units (HU) from CT images, including a mathematical parameter to calculate a ratio of hypervascular tumor rim thickness to tumor diameter. Transcriptomic analysis of 11 pts was performed to explore mRNA expression related to tumor vasculature. Kaplan-Meier analysis for progression-free survival (PFS) and ANOVA for statistical comparisons were applied. Results: The median age was 60 years, and 41 pts were female. For FGFR2-fused iCCA, median PFS for first-line gemcitabine-based chemotherapy with or without immunotherapy was 4.07 months [3.0-5.1]. Among FGFR inhibitors, mPFS was 7.07 months [95% CI: 5.10-8.16], with no significant difference in outcomes between FGFR inhibitors. 59 pts had comparable CT images and were grouped into 3 groups based on K-means clustering: Group 1 (n=30) had mPFS of 3.07 months [2.03-4.10]; Group 2 (n=22), mPFS of 9.10 months [8.2-11.2]; Group 3 (n=7), mPFS of 34.03 months [18.2-37.6]. Group 1 had the most hypovascular tumors (the lowest HU in the periphery of tumors), while Group 3 had the most hypervascular tumors (p=0.017). The HU ratio of the hypervascular tumor rim thickness to tumor diameter showed a trend, with the highest ratio in Group 3 and the lowest in Group 1 (p=0.09). Transcriptomic analysis revealed a trend toward higher VEGF/VEGFR gene expression in hypervascular tumors. Eight pts received second-line FGFR inhibitors, with mPFS of 5.0 months [2.1-8.3]. Conclusions: Pts with FGFR2-fused iCCA have a shorter PFS on first-line chemotherapy, and PFS outcomes for FGFR inhibitors were consistent with existing data. Tumor vascularity, as assessed by CT imaging, may be a valuable predictor of response to FGFR inhibitors. This study suggests that hypervascular tumors may have better outcomes, warranting further investigation in a larger cohort to confirm these findings and establish tumor vascularity as a predictive biomarker for FGFR inhibitor therapy.

Clinical outcomes of camrelizumab + rivoceranib vs sorafenib (CARES-310) as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) of non-viral and viral etiology.

578 Background: CARES-310 (NCT03764293) evaluated the combination of PD-1 inhibitor, camrelizumab (cam), and VEGFR-1-3 inhibitor, rivoceranib (rivo), compared to sorafenib (sor) for the treatment of uHCC. Cam + rivo significantly improved median overall survival (mOS) and median progression-free survival (mPFS) compared to sor (mOS, 23.8 months [mo] [95% CI 20.6, 27.2] vs 15.2 mo [95% CI 13.2, 18.5] hazard ratio [HR] 0.64 [95% CI 0.52, 0.79]; one-sided p<0.0001; mPFS, 5.6 mo [95% CI 5.5, 7.4] vs 3.7 mo [95% CI 3.1, 3.7]; HR 0.54 [95% CI 0.44, 0.67]; one-sided p<0.0001). The most common (≥10%) grade ≥3 treatment-related adverse events in the cam + rivo arm were hypertension (38.6%) and AST increased (20.2%). Methods: A post-hoc analysis of CARES-310 was performed, where mOS and mPFS were estimated using the Kaplan-Meier method and compared between the 3 etiology groups of non-viral, hepatitis C virus (HCV), and hepatitis B virus (HBV) using the log-rank test. Results: mOS was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.68 [95% CI 0.39, 1.19]), HCV (HR 0.37 [95% CI 0.162, 0.84]), and HBV etiologies (HR 0.70 [95% CI 0.55, 0.89]) (Table). Similarly, mPFS was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.55 [95% CI 0.34, 0.91]), HCV (HR 0.50 [95% CI 0.23, 1.06]), and HBV etiologies (HR 0.57 [95% CI 0.45, 0.72]) (Table). Conclusions: Cam + rivo in CARES-310 suggested clinically meaningful mOS benefit in non-viral and viral HCC vs sor and provides assurance of clinical benefit for first line treatment to patients with uHCC independent of etiology. Clinical trial information: NCT03764293 . Etiology Group Camrelizumab + Rivoceranib (n=272) Sorafenib(n=271) Non-viral, n (%) 42 (15.4%) 45 (16.6) mOS, mo (95% CI) 26.8 (10.3, NR) 15.2 (9.6, 23.2) mPFS, mo (95% CI) 6.1 (4.1, 13.8) 3.7 (2.4, 5.5) HCV, n (%) 22 (8.1) 29 (10.7) mOS, mo (95% CI) 31.7 (10.8, NR) 13.3 (8.0, 21.5) mPFS, mo (95% CI) 12.7 (3.7, NR) 3.7 (1.8, 9.1) HBV, n (%) 208 (76.5) 197 (72.7) mOS, mo (95% CI) 23.0 (18.9, 26.0) 15.6 (13.3, 19.2) mPFS, mo (95% CI) 5.6 (5.5, 7.3) 3.7 (2.7, 3.7) HCC, hepatocellular carcinoma; mOS, median overall survival; mPFS, median progression-free survival; mo, months; HR, hazard ratio; HCV, hepatitis C virus; HBV, hepatitis B virus, NR, not reached. Results used Cox proportional hazard model. Confidence Intervals (CI) used the Brookmeyer and Crowley method.

Development and validation of the SPEAR scoring model and predicting overall survival in unresectable hepatocellular carcinoma patients treated with TACE, molecular targeted therapies, and immune checkpoint inhibitors.

533 Background: To develop and validate a predictive model to identify hepatocellular carcinoma (HCC) patients likely to benefit from combined treatment of transarterial chemoembolization (TACE), molecular targeted therapies (MTTs), and immune checkpoint inhibitors (ICIs). Methods: Data from 500 patients with unresectable HCC treated with TACE, MTTs, and ICIs (2019-2023) were analyzed. Patients were divided into a training set (241 from Nanfang Hospital) and a validation set (259 from various hospitals). Key prognostic variables were identified using random forest survival analysis, and the top five were used to construct a Cox proportional hazards model. Model performance was assessed using time-dependent AUC values, calibration curves, clinical decision curves (DCA), and net reclassification improvement (NRI) indices. Risk scores and optimal cut-off values for risk stratification were determined and validated. Results: Five key survival variables were identified: serum alpha-fetoprotein (AFP), red cell distribution width coefficient of variation (RDW-CV), aspartate aminotransferase (AST), platelet-to-lymphocyte ratio (PLR), and extrahepatic metastasis (EHM). The Cox model had a C-index of 0.694 in the training and 0.691 in the validation set. The training set's 1-year, 2-year, 2.5-year, and 3-year AUC values were 0.77, 0.73, 0.73, and 0.72, respectively, and 0.74, 0.74, 0.76, and 0.66 in the validation set. The ARAPE model demonstrated a more significant net benefit than existing models. Median overall survival (mOS) was 33.9 months for low-risk, 20.4 months for intermediate-risk, and 14.2 months for high-risk groups in the training set; in the validation set, mOS was 30.8, 18.7, and 10.5 months, respectively. Conclusions: The SPEAR model (Serum AFP, PLR, EHM, AST, and RDW-CV) model effectively stratifies risk for HCC patients receiving TACE combined with MTTs and ICIs, aiding in personalized treatment decisions.

Outlook for medicines development and use in 2025

Integrative computational analysis of anti-influenza potential in Caesalpinia mimosoides Lamk hydroethanolic extract

Recent advances in the synthesis and application of biomolecular condensates

Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .

Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses.

520 Background: In the phase 3 CheckMate 9DW study (NCT04039607), 1L NIVO + IPI demonstrated significant overall survival (OS) benefit vs LEN/SOR, higher objective response rate (ORR) with durable responses, and manageable safety in uHCC. We present efficacy by best overall response (BOR) subgroups and baseline characteristics, and additional safety analyses from the preplanned interim analysis. Methods: Patients (pts) with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5 or 6, and ECOG performance status 0 or 1 were randomized 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles), then NIVO 480 mg Q4W or LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was OS; secondary endpoints included ORR and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: A total of 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333). At a median follow-up of 35.2 (range 26.8–48.9) months (mo), median OS (95% CI) was 23.7 (18.8–29.4) mo with NIVO + IPI vs 20.6 (17.5–22.5) mo with LEN/SOR (HR 0.79 [95% CI 0.65–0.96]; P = 0.0180). ORR (95% CI) per BICR was significantly higher with NIVO + IPI vs LEN/SOR (36% [31–42] vs 13% [10–17]; P < 0.0001); median DOR (95% CI) was 30.4 (21.2–not estimable [NE]) mo vs 12.9 (10.2–31.2) mo. Survival benefit of NIVO + IPI vs LEN/SOR was observed across BOR subgroups at the 24-week landmark timepoint (Table). In subgroup analyses, ORR (95% CI) per BICR was higher with NIVO + IPI vs LEN/SOR across HCC etiologies (uninfected: 35% [26–44] vs 8% [4–15]; HBV infected: 25% [17–34] vs 17% [10–25]; HCV infected: 50% [39–61] vs 16% [9–25]) and in pts with Barcelona Clinic Liver Cancer stage ≤B (33% [23–43] vs 13% [6–21]) or stage C (37% [31–44] vs 14% [10–19]). Safety data are shown in the Table. Additional exploratory analyses will be presented. Conclusions: These additional analyses from CheckMate 9DW demonstrate the efficacy and manageable safety of 1L NIVO + IPI in uHCC and further support its use as a potential standard-of-care treatment option in this setting. Clinical trial information: NCT04039607 . OS by BOR at week 24 landmark NIVO + IPI LEN/SOR BOR CR + PR (n = 101) SD a (n = 105) PD (n = 47) CR + PR (n = 28) SD a (n = 212) PD (n = 31) Median OS (95% CI), mo NR (44.4–NE) 30.0(23.5–37.8) 16.0(12.0–18.7) 28.3(20.6–NE) 22.5(20.5–24.8) 13.5(8.7–25.3) All treated pts NIVO + IPI (n = 332) LEN/SOR (n = 325) Any-grade/grade 3–4 TRAEs, n (%) 278 (84)/137 (41) 297 (91)/138 (42) Hepatobiliary 44 (13)/35 (11) 15 (5)/10 (3) Cardiovascular 10 (3)/3 (< 1) 138 (42)/39 (12) Hemorrhagic 2 (< 1)/1 (< 1) 20 (6)/5 (2) a Includes non-CR/non-PD. CR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event.

Quality of life following complete clinical response to chemoradiotherapy for rectal cancer: Patient-reported outcomes.

120 Background: Complete clinical response (cCR) after neoadjuvant therapy (chemoradiotherapy/total neoadjuvant treatment) for rectal cancer may permit an organ-preserving approach with “watch and wait” (W&W) surveillance. This confers comparable survival, while avoiding the sequelae of pelvic surgery. Data on quality of life (QOL) for this cohort are lacking. Methods: Patient-reported outcomes were collated for patients on W&W following cCR in a single hospital network. Validated questionnaires evaluating surgical, radiation and chemotherapy-related QOL were completed, including Low Anterior Resection Syndrome (LARS) score, Functional Assessment of Chemotherapy: Colorectal (FACT-C), EORTC QLQ-CIPN20, EQ-5D-5L and a linear analogue and ordinal scale ranking self-perception of health. Results: From 2016-2023, 76 patients were enrolled on W&W. Median follow-up is 37 months (IQR20-63). 12 patients (15.8%) had local regrowth, of whom 11 (92%) had salvage surgery. Five patients (6.5%) developed metastases at median 8 months (IQR3-12) from W&W entry. Of 57 patients (75%) with sustained cCR on surveillance, 44 (77%) responded to structured questionnaires. Two with stomas were excluded from LARS. 74% of respondents had no LARS, 9% minor LARS and 17% major LARS. 43% reported faecal urgency and 33% faecal incontinence. 41% experienced functional impairment due to chronic chemotherapy-related side effects (Table). Median EORTC CIPN20 score was 23 (IQR20-28; possible range 19-76, high score = poor QOL). Median sensory score was 11 (IQR9-15.5, PR 9-36), median motor score 8 (IQR8-11, PR 8-32) and median autonomic score 4 (IQR3-6) for males (PR 3-12) and 2 (IQR2-2.5) for females (PR 2-8). 54% of men reported erectile dysfunction, of whom 62% experienced severe dysfunction (33% of all males). Median FACT-C score was 123.5 (IQR108-131; PR 0-136, high score = better QOL). Median overall health score was 80% (IQR70-95). 36% of patients reported difficulty with mobility, 27% with usual activities and 11% with self-care. 30% declared ongoing physical pain/discomfort, while 23% live with anxiety/depression related to their diagnosis. Overall, 86% of reported problems were mild/moderate and 14% severe/very severe. Conclusions: This study highlights self-reported QOL in patients on W&W pathway following neoadjuvant treatment of rectal cancer. It provides important insight to side-effects of treatment escalation in hope of organ preservation, and presents vital information for the counselling of future patients. Patients (n=41) Upper limb paraesthesia 12 (29%) Lower limb paraesthesia 17 (41%) Difficulty with: - Walking/standing (foot drop or impaired sensation) 10 (24%) - Stairs/sit-to-stand (leg weakness) 11 (27%) - Hot/cold differentiation 4 (10%) - Holding pen/manipulating small objects/opening jar/bottle 12 (29%) Hearing impairment 13 (32%) Blurred vision 4 (10%)

Clinical landscape of cell free DNA alterations in patients with advanced biliary tract cancer treated with targeted therapies.

626 Background: Although 40% of patients (pts) with advanced biliary tract cancer (BTC) harbor actionable alterations amenable to targeted therapy (TT), tumor genotyping can be challenging due to limited tissue and other factors. Next generation sequencing (NGS) of cell free DNA (cfDNA) may aid in prognostication, identification of TT opportunities, and characterization of acquired resistance mechanisms to TT. Methods: cfDNA was collected prospectively in pts with BTC treated at MSK from 2016-2023. Samples were analyzed using a CLIA-approved, cfDNA targeted NGS assay (MSK-ACCESS). When available, matched tumor samples were analyzed using an FDA-authorized targeted NGS assay (MSK-IMPACT). Objectives included evaluating association of cfDNA genomic alteration variant allele frequency (VAF) with outcomes and description of genomic features identified on cfDNA at resistance to TT. Results: N=170 BTC pts (intrahepatic cholangiocarcinoma [CCA], n=121; extrahepatic CCA, n=29, gallbladder cancer, n=20) underwent cfDNA genotyping, comprising 270 samples overall. A majority of pts (146/170, 86%) had locally advanced or metastatic disease. OncoKB level 1/2 alterations were identified in 19% of pts overall. Pts with treatment-naïve locally advanced or metastatic BTC whose baseline detected cfDNA genomic alterations were VAFhigh (defined as > median VAFmax across all samples, n=60) had significantly worse median PFS (4.5 (95% CI 2.2-6.5) vs. 11.8 (95% CI 5.4-18.4) months, (HR 2.7, p=0.002) and OS (14.1 (95% CI 5.4-19.9) vs. 32.0 (95% CI 13.8-39.9) months, HR 3.1, p=0.002)) to first line treatment. Serial cfDNA was available from 28 pts who received TT. Emergent RAS isoform alterations were identified at resistance in 7/25 (28%) pts who received BRAF-, FGFR-, or HER2-directed TT. These included 3/5 pts who received BRAF/MEK TT for BRAF V600E+ BTC (emergent KRAS G12D in 1, NRAS Q61K in 1, polyclonal KRAS G12D, G12V, G13D in 1), 2/13 pts who received FGFR TT for FGFR2 fusion+ BTC (KRAS Q61H in 1, NRAS Q61R in 1), and 2/7 pts who received HER2 TT for ERBB2-amplified BTC (KRAS G12C in 1, KRAS amp in 1). Serial cfDNA also revealed canonical FGFR2 resistance mutations in 3 pts who received FGFR TT, as well as loss of index ERBB2 amp in 2, acquired ERBB2 resistance mutation in 1, acquired MYC amp in 2, and MET amp in 1 pt who received HER2 TT. Conclusions: cfDNA NGS in pts with BTC may assist with prognostication in advanced disease and can identify novel patterns of resistance, including frequent emergence of RAS alterations at resistance across multiple TTs. These may identify therapeutic opportunities for KRAS- and NRAS-directed therapeutics in development, and underscore the importance of serial cfDNA profiling.

In-situ observation of nanoscale transformations in dehydrating lizardite