Death In Pts Research Articles

Abstract PO2-06-07: A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer

Abstract Background: Both TNBC and BRCA-1 associated breast cancers are sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. TNBCs are also associated with a high frequency of PTEN loss, which can lead to activation of the mTOR pathway resulting in tumor cell growth and proliferation. mTOR activation can confer resistance to platinum agents, and this phenomenon may be reversible by the addition of an mTOR inhibitor, such as everolimus. A prior phase II single arm trial of carboplatin and everolimus in patients (pts) with advanced TNBC demonstrated good tolerability and preliminary efficacy. Methods: We conducted a phase II, multicenter, randomized trial in pts with advanced TNBC, who had received 0-3 prior lines of therapy. Pts were randomly assigned (in a 2:1 ratio) to carboplatin and everolimus or carboplatin alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. We planned to enroll 72 pts which would provide > 80% power for a one-sided log-rank test at the 5% level of significance, to detect a 2.5 month improvement in median PFS between treatment groups, assuming a median PFS of 2.5 months in the control group. An interim analysis for futility was planned after 36 events with a stopping boundary of P <0.375 for the comparison of PFS, using an Obrien-Fleming spending function. Of note, the trial was stopped earlier than planned based on a sensitivity/tipping point analysis which indicated that terminating the trial 3 months ahead of schedule would have no substantial impact on the primary endpoint. Results: A total of 56 pts were randomized between 2015 and 2022, of whom 36 received carboplatin/everolimus and 20 carboplatin alone. The median age of the population was 62.8 years (range: 33-87) and about 20% of pts had BRCA-1 or BRCA-2 mutations. In the overall population, pts had received a median of 1 (range 1-3) prior line of therapy in the metastatic setting, with 75% of pts receiving prior chemotherapy and 47% prior carboplatin. The median PFS was significantly improved in pts who received carboplatin and everolimus (4.7 months) versus those who received carboplatin alone (2.1 months; HR: 0.37; 95% CI: 0.19-0.72; p=0.0042). Overall survival was 22.1 months in pts on the combination versus 14.4 months on carboplatin alone (HR: 0.73; 95% CI: 0.30-1.72; p=0.3106). CBR was 61% with the combination vs 50% with carboplatin monotherapy, as shown in Table 1. Most common adverse events (AEs) on carboplatin and everolimus included thrombocytopenia (81%), anemia (69%), leukopenia (67%), fluid retention (64%), and neutropenia (61%). Overall, Grade 3/4 events occurred in 75% of pts (83% of pts on combination vs 60% on carboplatin alone) and were primarily anemia (40% vs 17%), thrombocytopenia (47% vs 0%), and neutropenia (20% vs 0%). Of note, there was an increase in thrombocytopenia with the addition of everolimus (All Grades: 81% vs 35%, Grade 3/4: 39% vs 0%). Conclusions: Treatment options for TNBC are limited due to a lack of targeted therapies. The combination of carboplatin and everolimus in this study was associated with a 63% reduction in risk of progression or death in pts with metastatic TNBC. The regimen was well tolerated and provides a promising treatment option for pts with advanced TNBC. Table 1. Results in Patients on Carboplatin and Everolimus versus Carboplatin Alone NE= Not Estimable; 1Unevaluable patients treated as non-responders in CBR and ORR calculations. Citation Format: Rima Patel, Jami Fukui, Paula Klein, Erin Moshier, Charles Shapiro, Anupama Goel, Julie Fasano, Theresa Shao, Aarti Bhardwaj, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-07.

Five-Year Follow up Results of Phase II Clinical Trial Evaluating Ruxolitinib (RUX) and Azacitidine (AZA) Combination Therapy in Patients (pts) with Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

Introduction: MDS/MPN represent a distinct category of Philadelphia chromosome negative myeloid neoplasms that share pathological and morphological characteristics with both MDS and MPN. Very few prospective studies have been conducted in pts with MDS/MPN, with currently available data showing a median overall survival (OS) of less than two years in this challenging subset. We conducted a phase 2 clinical trial evaluating the combination of JAK-inhibitor RUX with demethylating agent AZA in pts with MDS/MPN. The interim analyses (Assi et al, AJH 2018) showed objective responses in 57% pts and a median duration of response (DOR) of 8 months (mos). Herein we report the long-term follow up of a larger cohort of pts treated on this prospective ongoing clinical trial. Methods: We conducted an open label single-arm phase 2 clinical trial (NCT01787487) at the MD Anderson Cancer Center, Houston, evaluating the use of RUX-AZA in newly diagnosed or previously treated MDS/ MPN. Adults aged ≥ 18 years with MDS/MPN categorized as Intermediate 1-2 or High-risk by Dynamic International Prognosis Scoring System (DIPSS) (Passamonti et al, Blood 2010) were included. Pts previously exposed to RUX and/or AZA were excluded. RUX 5-20mg twice daily (per RUX label depending upon platelet counts at initiation) was given in 28-day cycles, and AZA 25mg/m2 (SQ or IV) Days 1- 5 was added starting cycle 4. Cycles were repeated every 4-6 weeks depending on count recovery. Response assessment was carried out using the 2015 International Consortium Proposal of response MDS/MPN criteria (Savona M et al, Blood 2015) and best objective response was tabulated. Progression free survival (PFS) included treatment change because of disease progression or inadequate response, transformation to acute myeloid leukemia (AML) or death and calculated from the time of therapy initiation. Results: From May 2013 to August 2022, 52 pts with a median age of 68 years (range, 39-82 years) were treated on trial. The data cutoff was July 15, 2023 ( Table 1). 32 pts (61%) were males, and 9 (75%) pts were white. 50 pts (96%) had ECOG PS<2. Baseline median bone marrow (BM) blasts were 4.5% (range 0-19%), with 19 (37%) carrying JAK2 mutations, and 16 (31%) with an abnormal karyotype. Intermideate-2 DIPSS was the most prevalent risk category, seen in 23 (44%) pts. At least one cytopenia was present in 32 (61%) pts, and three (6%) pts had bicytopenia. 24 of 49 (49%) had palpable splenomegaly, and 3 pts had undergone prior splenectomy. After a median follow up of 60 months (mos) (95% CI: 50.0-71.3) from therapy initiation, 18 (35%) pts are alive, and 1 pt is on active trial therapy. Objective responses per the MDS/MPN international consensus response criteria were observed in 28 (54%) pts and included clinical improvement in 14 (50%) pts, partial marrow response in 12 (43%) pts, optimal marrow response and cytogenetic complete remission in 1 (4%) pt each. The DOR in the 28 pts with objective response to therapy (censored for death in pts who died without evidence of progression) was 35 mos (95% CI: NE-73.5). The median OS in this group of responders was 36.4 mos (95% CI: NE-77.2). Five of these pts died without confirmed disease progression at the time of death. For the full cohort the median PFS was 13.4 mos (95% CI: 7.9-18.8) and median OS was 31.8 mos (95% CI: 18.5-44.9 ) (Figure 1). Transformation to AML occurred in 12 (23%) pts, with the median time to transformation being 13.2 mos (range 2.9-71.3) and all of them have died at the time of last follow-up. 8 (15%) pts underwent allogenic stem cell transplant (ASCT) as subsequent therapy following treatment with AZA-RUX amongst whom 6 (75%) had shown objective responses prior to transplant. For the pts who underwent ASCT, median PFS from the initiation of AZA-RUX was 40.8 months and median OS was not reached. Conclusion: Long term follow up from this phase II prospective clinical trial demonstrates durable disease responses with the RUX-AZA combination in MDS/MPN, with the responses translating into improved survival outcomes.

Overall survival and causes of death in elderly patients with Hodgkin lymphoma—a Norwegian population‐based case‐control study

Background: Elderly Hodgkin Lymphoma (HL) patients (pts) are poorly characterized and underrepresented in high-quality studies. Populations-based studies with individual disease- and treatment-factors together with causes of death are lacking. Methods: Pts ≥60 years diagnosed with HL between 2000 and 2015 were identified by Cancer Registry of Norway. Hospital and other health-care records were reviewed and pts grouped according to treatment into ineligible (no HL directed treatment), palliative (intended dose intensity <50%) or curative (>50% intended dose intensity of HL regimens or curative radiotherapy only). Pts’ causes of death were obtained from records and compared to The Norwegian Cause of Death Registry providing date and cause of death for pts and cancer-free controls matched 1:10 based on age, sex and place of residency. Overall survival was analyzed by Kaplan-Meier statistics. Cumulative incidence functions were calculated using the Aalen-Johansen estimator and compared using Gray’s test. Risk differences between pts and controls were calculated for each competing event at 2, 5 and 10 years. Results: Of 492 pts, 81 (16.5%) were ineligible for the analysis of treatment outcomes, due to composite lymphoma (n = 51), diagnosis after death (n = 13), severe comorbidity (n = 16) or incomplete patient data (n = 7). 74 (15%) and 337 (68.5%) pts were treated with palliative or curative intent, respectively, most commonly with CHOP. Median overall survival in the ineligible, palliative and curative groups were 0.5 (95% Confidence interval [CI] 0.4–0.6), 0.8 (0.4–1.2) and 9.1 (7.5–10.7) years, respectively. With 359 deaths, the most common cause was HL in all groups, with 30% dying from HL, 8% from treatment-related mortality and 62% from other causes. The risk difference of dying from HL compared to controls increased from 16% (95% CI: 12%–20%) at 2 years to 28% (23%–33%) after 10 years for the curative group, compared to 59% (48%–71%) and 42% (31%–53%) after 10 years in the palliative and ineligible groups, respectively. There was an increased risk of dying from other hematological malignancies, including Non-Hodgkin lymphoma in all groups, but not from other causes of death (Figure 1). Keyword: Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Abstract CT065: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress)

Abstract Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4-8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by blinded independent central review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan-Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, and several EU and APAC countries, with additional sites planned. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Joohyuk Sohn, Giuseppe Curigliano, Ciara C. O’Sullivan, Miguel Martín, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Veronique Dieras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT065.

Abstract OT2-16-03: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress)

Abstract Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara C. O’Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-03.

Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.

4 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings. Methods: The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS). Results: Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P&lt; 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P&lt; 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted. Conclusions: FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187 .

P1328: SUCCESFUL TREATMENT OF GRAFT FAILURE IN AUTOLOGOUS STEM CELL TRANSPLANTATION WITH CYCLOSPORINE

Background: Graft failure is an unusual complication of autologous stem cell transplantation (ASCT). It is a life threatening complication where most patients (pts) die because of infections or bleeding. It is defined by absence of neutrophil recovery (>500 ANC) on day +28. It can be primary (there wasn´t a previous neutrophil recovery) or secondary (if there was). Ruling out infections, toxicity of conditioning or poor quality of cells infused, the main cause is still unknown. There is no much literature about GF in ASCT. Treatments proposed are cellular reinfusion or search of a donor for allogeneic stem cell transplantation with poor results. Aims: The aim of this study is to describe our experience in treating such a rare ASCT complication. Primary endpoint is the obtainment of neutrophils (>500) and the platelet engraftment (>20.000) with no transfusion-dependence. Methods: Between 2010 and 2021 a total of 706 pts underwent an ASCT in our institution. 5 pts presented a primary (n=4) or secondary (n=1) GF. We collect the data from these patients. Results: Our incidence of GF is 0.71%, making GF a rare complication of ASCT. 4 pts had a primary GF and 1 had a secondary GF. Peripheral blood was the source in the pts; who were mobilized with G-CSF without any complication. All the pts were infused with more than 2 x106 CD34+ cells /kg (median number of 2.7 (2.2 -3.4)) without any manipulation of the graft. The median viability was 96% (92-99.7). None of the pts had splenomegaly or bone marrow infiltration at the moment of ASCT. These 5 pts had different hematological diseases (3 Multiple Myeloma (MM), 1 composite lymphoma (CL) and 1 primary nervous system lymphoma (PCNSL)). The status of response at ASCT was 3 CR, 1 VGPR (1 MM) and 1 PR (PCNSL). The conditioning regimen used was BUMEL (2 MM), MEL200 (1 MM) BEAM (1 CL) and TT-BCNU (1 PCNSL). All the pts received G-CSF from day +5 after cell infusion. Bone marrow biopsy was made in 3 of these pts, with severe hypoplasia without fibrosis. After diagnosis of GF, in all the pts, the first line treatment was increased dose of G-CSF. 4 pts were also treated with corticoids without any response. 2 pts additionally received previously cryopreserved cells without response. We started empiric treatment with CsA at an initial dose of 1.5mg/kg twice daily in these pts and the median time to reach>500 ANC was 5 days (4-9). Three of these pts could stop CsA treatment after 30 days due to recovery of neutrophil and platelet count. Another one had to be under treatment 150 days. The last one is still on treatment (after 2 months). With a median follow up of 90 months (2-91) all the pts are alive and with a good neutrophil and platelet engraftment. In terms of security, 2 pts developed mild renal failure, managed by dose adjust. No other adverse events were seen in these pts. Summary/Conclusion: CsA is an immunosuppressive drug widely used in aplastic anemia and other bone marrow failure syndromes, due to suppression of haematopoiesis by autoreactive T- lymphocytes. This can also be the pathogenic mechanism of GF. We successfully used empirical CsA treatment in these pts. All the pts but one had an ANC>500 in the first week of treatment with CsA and were able to discontinue the drug soon. Severe infections due to neutropenia are the first causes of death in pts with GF so improvement of ANC decrease is the main goal in the treatment of GF. As CsA is a secure drug, we propose to urgently include this treatment as a curative option in the algorithm of GF management to be taking into account before the allogeneic stem cell trasplantation option.

Abstract 4118: Brain metastases (BM) and next-generation sequencing (NGS) timing: Real-world (RW) outcomes for patients (pts) with advanced non-small cell lung cancer (aNSCLC) and MET exon 14 skipping mutations (METex14)

Abstract Background: Treatment (Tx) options for METex14 NSCLC have been limited to chemotherapy (Ctx), immunotherapy (IO), and multikinase inhibitors (MKi) until FDA approvals of selective MET inhibitors (METi) from 2020. BM are a further challenge to treat. We previously reported NGS timing in relation to start of first-line Tx (1L) for pts with METex14 NSCLC in the RW. Here we provide overall survival (OS) data, including subgroup analyses for pts with known BM prior to 1L initiation. Methods: Data originating from ~280 US cancer clinics (~800 sites of care) from the US electronic health record-derived de-identified Flatiron Health Foundation Medicine clinico-genomic database (FH-FMI CGDB) were evaluated. Pts were ≥18 yrs, diagnosed with advanced/metastatic NSCLC from Jan 1, 2011, with NGS-confirmed METex14, ≥1 line of Tx, and ≥90 days follow-up from 1L initiation to cutoff date (Dec 2020). Pts treated with capmatinib or tepotinib were excluded. We examined Tx patterns and OS for pts with and without known BM before starting 1L, and OS for pts with an NGS report before or on/after 1L initiation (time from 1L initiation to death or censoring, analyzed using Kaplan-Meier method with left truncation adjustment to mitigate bias due to the prerequisite for NGS testing). HRs were estimated using Cox regression models with covariates adjustment to estimate risk of death. Results: The analysis included 156 METex14 NSCLC pts: median age 75 yrs, 59% females, 85.3% non-squamous (NSQ), 9% squamous cell carcinoma (SQ), and 64% had history of smoking. A total of 31 pts (20%) had BM before 1L initiation: median age 73 yrs, 61% females, 94% NSQ, 0% SQ, and 71% had history of smoking. Overall, treatment patterns were similar for pts with and without known BM before 1L initiation (Ctx with or without IO, IO monotherapy, and MKi were all used in 1L). Median OS for pts with BM was 8.11 mo (95% CI, 6.0-19.8) and 14.39 mo (11.1-22.1) for pts without BM, corresponding to a 73% increase in risk of death for pts with BM vs pts without BM by univariate analysis (HR 1.73 [95% CI, 1.06-2.82]; P=0.03). Median OS for pts with an NGS report before and on/after 1L initiation was 13.3 mo (8.8-26.2) and 6.8 mo (0.03-19.8), respectively (P=0.45); HR by multivariate analysis was 0.78 (0.45-1.35) when comparing pts with NGS report before vs on/after 1L initiation. Conclusions: Tx patterns in 1L were similar for pts with or without BM at time of 1L initiation; presence of BM prior to 1L was associated with inferior outcomes. Numerically longer OS was observed in pts with NGS report prior to 1L initiation vs pts with NGS report on/after 1L, supporting further investigation of underlying causes. These data underline the ongoing unmet clinical need of METex14 NSCLC BM and the importance of investigating upfront comprehensive genomic testing in NSCLC. Citation Format: Xiuning Le, Stephen Robb, Nydia Caro, Simona Doria, Whitney C. Rhodes, Wen-Hsing Wu, Julia Kim, Vincent Prêtre, Fen Ye. Brain metastases (BM) and next-generation sequencing (NGS) timing: Real-world (RW) outcomes for patients (pts) with advanced non-small cell lung cancer (aNSCLC) and MET exon 14 skipping mutations (METex14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4118.

Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress).

TPS1108 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Clinical trial information: NCT05132582.

The prognostic role of nephrectomy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with immunotherapy according to the novel prognostic Meet-URO score: Subanalysis of the Meet-URO 15 study.

4535 Background: Most of mRCC pts with favorable and intermediate prognosis, according to the IMDC classification, are offered a nephrectomy. However, in the immunotherapy era, the role of nephrectomy is still unclear. In the Meet-URO 15 study we reported the higher prognostic accuracy of the Meet-URO score compared to the IMDC score, by the addition of the neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases to the IMDC score, identifying five categories with progressively worse prognosis. For this reason, we aimed to explore the prognostic impact of the previous nephrectomy (PN) on mRCC pts receiving immunotherapy and according to the Meet-URO score groups. Methods: The Meet-URO 15 study was a multicentric retrospective analysis on 571 pretreated mRCC pts receiving nivolumab. Univariable analysis of the correlation between PN and overall survival (OS) and multivariate analysis adjusted for IMDC score, therapy line, NLR and metastatic sites were performed. The interaction of PN with the Meet-URO prognostic groups was then evaluated. Results: 503/571 pts (88%) underwent PN. A reduced risk of death (HR = 0.44; 95% CI: 0.32-0.60; p&lt; 0.001) and higher mOS and OS rate were observed in pts with PN than without (mOS: 36 vs 13 monhts; 1-year-OS 72% vs 52% and 2-year-OS 57% vs 24%, respectively). The reduced risk of death for pts who underwent PN was confirmed at the multivariate analysis (HR = 0.69; 95% CI: 0.49-0.97; p= 0.032). The percentage of pts receiving PN progressively reduced through the five Meet-URO prognostic groups (PN: group 1: 98%, group 2: 95%, group 3: 84%, group 4: 79%, group 5: 59%). No significant interaction was observed between the PN and Meet-URO score when all the five groups were considered ( p= 0.17). A significant interaction was observed when the Meet-URO groups 1,2 and 3 were taken together (HR = 0.40; 95% CI: 0.25-0.63; p&lt; 0.001), highlighting the significant protective role of the PN on OS for these three groups. For the Meet-URO groups 4 and 5, the interaction was indeed not significant (HR = 0.81; 95% CI: 0.51-1.30; p= 0.39). Conclusions: PN has a favourable prognostic impact on pretreated mRCC pts receiving immunotherapy. This benefit may be limited to mRCC pts with more favorable diseases as belonging to Meet-URO prognostic groups 1, 2 and 3. Further analysis of the type of PN (i.e., radical vs cytoreductive) is ongoing and confirmatory prospective evaluations are warranted.

Comparison of survival outcomes between dostarlimab and comparator treatments (tx) in patients (pts) with advanced/recurrent (A/R) endometrial cancer (EC) in England: Matching-adjusted indirect comparisons (MAICs).

e17534 Background: Limited tx options exist for pts with A/R EC who progress on/after platinum-based chemotherapy (PBCT). This study compared survival outcomes of pts with A/R mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC receiving dostarlimab in Cohort A1 of the single-arm, Phase I GARNET trial, with an equivalent real-world (RW) cohort receiving current tx in England. The primary objective compared second-line (2L) overall survival (OS) between cohorts; a secondary objective was time to tx discontinuation (TTD; proxy for progression-free survival). Methods: An overall-2L-tx RW cohort was established using National Cancer Registration and Analysis Service data. Five tx-specific RW cohorts were identified (tx received at 2L in &gt; 5% of pts) (Table). Clinical outcomes between GARNET and RW cohorts were compared using MAICs. Relevant prognostic variables were used to create 3 matching scenarios (SC): SC1: grade, histology, PBCT number; SC2: histology, PBCT number; SC3: race/ethnicity, stage at diagnosis, histology, prior surgery (MMR/MSI status not considered). OS was time from first dostarlimab dose (GARNET) or 2L RW tx (RW cohorts) to any-cause death; MAIC-adjusted hazard ratios (HR, 95% confidence interval [CI]) were estimated by weighted Cox proportional-hazards models. TTD after MAIC was summarized descriptively. Results: Effective sample size (ESS) assessed matching capacity; lower ESS in SC1 reduced its robustness (Table). Following matching, distributions of baseline characteristics were similar between cohorts. Across most matching scenarios, there was a lower risk of death in pts treated with dostarlimab compared to the overall RW cohort and for tx-specific RW cohorts (Table). Median TTD (months, 95% CI) was longer for pts treated with dostarlimab across all matching scenarios (SC1: 7.8 [4.1, not estimable (NE)]; SC2: 9.7 [5.5, NE]; SC3: 14.0 [6.4, 17.9]) than the overall RW cohort (3.4 [3.2, 3.4]). Conclusions: Results suggest that pts in GARNET with dMMR/MSI-H A/R EC receiving dostarlimab had better OS and longer TTD compared with pts receiving current 2L tx in England. Funding: GSK (217216; scott.r.goulden@gsk.com).[Table: see text]

Outcomes Following Heart Transplant for Patients with Cardiac Amyloidosis

<h3>Purpose</h3> Cardiac amyloidosis (CA) results from myocardial transthyretin (ATTR) or immunoglobulin light chain (AL) deposition and is associated with high mortality. Heart transplant (HT) has emerged as an option for patients (pts) with advanced disease. We present long-term survival data following HT for pts with CA. <h3>Methods</h3> All adult HT pts at our center between 1/1/2012 and 12/31/2020 were included. Heart explant pathology reports were reviewed for evidence of amyloid deposition based on Congo red staining. ATTR subtyping was confirmed with mass spectrometry analysis. Kaplan-Meier survival analysis was computed using a log-rank test for between-group differences. <h3>Results</h3> 63 pts with CA [AL (17), wild type - ATTR (20), variant - ATTR (24), amyloidosis leukocyte chemotactic factor 2 (1), beta 2 microglobulin (1)] underwent HT during the study period. Pts with CA were older (65.4 vs. 54.2), more likely to be male (90% vs. 70%), and less likely to be white (56% vs. 71%) compared to pts without CA. 9 ATTR pts (21%) and 5 AL patients (29%) underwent dual organ transplant. 5 patients with AL amyloidosis underwent subsequent autologous stem cell transplant (ASCT). Post-HT survival at 5 years was similar for pts with AL amyloidosis, ATTR amyloidosis, and other HT patients (n = 911) (p=0.67). AL and variant-ATTR pts had numerically lower survival than wild type - ATTR patients. Cause of death for pts with AL CA included primary graft dysfunction (1), complications related to ASCT (1), and anoxic brain injury (1). For pts with ATTR CA, cause of death included liver graft rejection (1), multi organ failure (1), respiratory failure (1), decompensated heart failure (1), and acute myocardial infarction (1). <h3>Conclusion</h3> Pts with CA that meet criteria for HT experience survival comparable to that for other indications. HT remains a viable option for CA pts with advanced disease, despite older age at the time of HT.

Abstract GS2-02: Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial

Abstract Background: Endocrine therapy(ET) plus CDK4/6 inhibitor (i) is the mainstay for the management of estrogenreceptor-positive (ER+)/HER2- mBC. However, most patients (pts) with ER+ mBCeventually experience disease progression, including development of ESR1mutations (mESR1). Elacestrant, an oral SERD, demonstrated preclinical activity,and clinical activity in a phase 1 trial in ER+ mBC, including responses in ptswith prior fulvestrant, CDK4/6i, and mESR1tumors (Bardia JCO 2021).. Methods: EMERALD(NCT03778931), a multicenter, international, randomized, open-label, controlledphase 3 trial, enrolled postmenopausal pts with ER+/HER2- mBC who had received 1-2prior lines of ET and ≤1 line of chemotherapy in the mBC setting and had prior progressionon a ET plus CDK4/6i. Pts were randomized 1:1 to elacestrant (400 mg orallydaily) or standard of care (SOC; investigator’s choice of fulvestrant or anaromatase inhibitor). Stratification factors included mESR1 status (by central lab), priorfulvestrant exposure, and presence of visceral disease. The study had 2 primary endpoints of progression-free survival (PFS), by blindedindependent review committee, in pts withtumors harboring mESR1 and in all pts (mESR1 or mESR1 notdetected). Secondary endpoints included: overall survival (OS), safety, tolerability,and quality of life. An alpha-value of 0.0475 was used to determine statisticalsignificance (2-sided using the truncated Hochberg procedure).. Results: EMERALD enrolled 477 pts(228 with mESR1) between Feb 2019 - Oct 2020, with 239 pts randomized toreceive elacestrant vs 238 pts to SOC. Demographics and disease characteristicswere well-balanced across treatment arms [median age: 63 yrs vs 63.5 yrs; 2prior lines: 46% vs 40.8%; prior CDK4/6i: 100% in both arms]. The study met bothprimary endpoints. There was a 30% reduction in the risk of progression ordeath in the elacestrant arm in all pts (HR=0.697 [95% CI: 0.552, 0.88]; P=0.0018),and a 45% (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005) reduction in therisk of progression or death in pts with mESR1.For both endpoints, results in key prespecified subgroups, including visceral metastases,number of prior lines of therapy, pretreatment with fulvestrant, and geographicalregion, were consistent with the overall outcome. The PFS rate at 12 months was 22.32% (95% CI: 15.24%, 29.40%)with elacestrant vs 9.42% (95% CI: 4.02%, 14.81%) with SOC in all pts, and26.76% (95% CI: 16.17%, 37.36%) vs 8.19% (95% CI: 1.26%, 15.12%) in the mESR1 subgroup. The prespecified interim OS analysis plannedat the time of the final PFS analysis (allocated2-sided alpha level of 0.0001) demonstrated a trend in favor of elacestrant inall pts (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in pts with mESR1(HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325). The final OS analysisis expected next year. Common (&amp;gt;10%) treatment-related adverse events (AEs) withelacestrant vs SOC included: nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%), mostlygrade 1/2. Treatment-emergent AEs leading to discontinuation of elacestrant orSOC were infrequent in both arms (6.3% and 4.4%). Grade ≥3 treatment-relatedAEs in the elacestrant arm vs SOC were 7.2% vs 3.1%, mainly driven by nausea(2.1% vs 0.9%). There were no treatment-related deaths in either group.. Conclusions:Elacestrant is the first oral SERD to demonstrate a statistically significantand clinically meaningful improvement of PFS vs SOC in a randomized phase 3study in pts with ER+/HER2- mBC in the 2nd/3rd-linesetting, including those whose tumors harbor mESR1. Elacestrant was well tolerated and hasthe potential to become the new standard of care for pts with ER+/HER2- mBC. Citation Format: Aditya Bardia, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frédéric Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Peter Vuylsteke, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Virginia Kaklamani, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, José García-Sáenz, Emilio Bria, Marina Cazzaniga, Janice Lu, Philippe Aftimos, Javier Cortes, Shubin Liu, Dirk Laurent, Maureen G. Conlan, Francois-Clement Bidard. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-02.

First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study

First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study

Abstract 394: Prognosis and molecular characteristics of patients with TRK fusion cancer in the 100,000 Genomes Project

Abstract Background: NTRK gene fusions are oncogenic drivers in various tumor types. Overall survival (OS) of patients (pts) with tumors harboring NTRK fusions compared to pts without is unknown, and data on co-occurrence of NTRK fusions with other oncogenic drivers are limited.1 Methods: This retrospective study used genomic data generated by the 100,000 Genomes Project with linked clinical data from UK cancer databases. Pts with cancer who had undergone tumor whole genome sequencing between Mar 2016 and Jul 2019 were included. OS of pts with and without NTRK fusions, matched by exact and distance matching with a 1:4 NTRK+:NTRK− ratio, was analyzed by Kaplan-Meier method and Cox regression. Key alterations in ALK, BRAF, EGFR, HER2, KRAS and ROS1, and tumor mutation burden (TMB) and microsatellite instability (MSI), were evaluated along with NTRK gene fusions. Results: Of 15,223 pts analyzed, 38 (0.2%) had NTRK fusions, identified in 11 cancers (Genomics England classification), the most common being breast cancer (n=9), colorectal cancer (CRC; n=9), and sarcoma (n=7). While there was no significant OS difference in pts with and without NTRK fusions, the HR was 1.47 (95% CI 0.39-5.57; Table). Of the tested oncogenic drivers, only KRAS mutation was identified in 2 (5%) pts with an NTRK fusion (both hepatobiliary cancer), while oncogenic driver frequency in pts without NTRK fusions ranged from 0.1-11.6%. High TMB was more common in pts with NTRK fusions than in those without (21% vs 6%), as was high MSI (18% vs 6%); all pts with NTRK fusions and high TMB and/or MSI had CRC. Conclusions: While no statistical difference in OS was observed, there was a trend to higher risk of death in pts with NTRK fusions compared to those without, consistent with a recent US study.1 Co-occurrence of NTRK fusions and other biomarkers was rare, except for high TMB and high MSI in CRC. These results highlight NTRK fusions as actionable biomarkers and emphasize the need for NTRK gene fusion testing. NTRK− (n=72†)NTRK+ (n=18†)Median follow-up (IQR), years2.28 (1.57-2.98)2.01 (1.40-2.97)Median OS (IQR), yearsNE (NE-NE)NE (NE-NE)Landmark OS, % (95% CI)1 year96 (91-100)94 (84-100)2 years94 (89-100)87 (71-100)3 years88 (78-99)87 (71-100)HR (95% CI)1.47 (0.39-5.57)†Only patients with linked clinical data and who were matched were included in the OS analysis.1CI, confidence interval; HR, hazard ratio; IQR, interquartile range; NE, not estimable; NTRK; neurotrophic tyrosine receptor kinase; OS, overall survival.1. Bazhenova L, et al. Clin Cancer Res. 2020;26(12 Suppl 1):09-09. Citation Format: John Bridgewater, Xiaolong Jiao, Mounika Parimi, Clare Flach, Jeran Stratford, Atanas Kamburov, Arndt Schmitz, Jihong Zong, John A. Reeves, Karen Keating, Amanda Bruno, Marc Fellous, Lyudmila Bazhenova. Prognosis and molecular characteristics of patients with TRK fusion cancer in the 100,000 Genomes Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 394.

CGvHD — CIBMTR Risk Score Stratification in 207 Consecutive Adults after Unmanipulated PBSC Haploidentical Stem Cell Transplantation

IntroductionSo far graft-versus-host disease (GvHD) is the most common long-term complication after allogeneic stem cell transplantation (HCT) and it decreases the success of HCT by increasing the risk of death and disability. Chronic GvHD (cGvHD) is the leading cause of non relapse mortality in HCT survivors.In 2011 the CIBMTR proposed a cGvHD risk score based on 10 variables - age, prior acute GvHD, time from HCT to cGvHD, donor type, disease status at HCT, GvHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score and platelet count - that provided stratification of patients (pts) into 6 risk groups (RG) with different outcome in terms of overall survival (OS) and non-relapse mortality (NRM). Recently the CIBMTR risk score was refined to enhance prognostic stratification with the incorporation of the absolute lymphocyte and eosinophil count at time of cGvHD onset.However, few recipients of haploidentical HCT (haplo-HCT) were originally included in the CIBMTR risk score cohorts.MethodsWe analyzed the original and revised CIBMTR risk score in haplo-HCT at our Center, where a sirolimus-based, calcineurin inhibitor-free, GvHD prophylaxis was employed since 2006, to allow the safe infusion of unmanipulated haplo-HCT.We analyze data consecutively collected between 2006 and 2014 including 207 adult pts. Data were prospectively collected in an Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki.All consecutive pts receiving a haplo-HCT as 1st allogeneic transplantation were included - pts receiving haplo-HCT as 2nd or 3rd HCT were excluded from the present analysis. All pts were prospectively evaluated for cGvHD according to the 2004 NIH consensus criteria.ResultsBaseline characteristics of the 207 pts are outlined in table 1.With 4-year median follow-up, 4-year probabilities of transplant related mortality (TRM), relapse, progression-free survival (PFS), and overall survival (OS) were 25,8%, 42,5%, 31,7%, and 34,4%, respectively. Considering the composite end point of GvHD/relapse free survival (GRFS), for the entire population the 4-year GRFS was 17,8%.Day-100 cumulative incidence of grade II-IV and III-IV acute GvHD were 30,1% and 15,5% respectively.The 4-year cumulative incidence of chronic GvHD was 33,5% (n 74) - moderate-severe chronic GvHD 26,2%.According to the original CIBMTR RG the 3-year OS in each RG was RG1 (n 1) 100%, RG2 (n 42) 83%, RG3 (n 26) 34% and RG4 (n 5) 20% (p < .0001).According to the revised CIBMTR RG the 3-year OS in each rRG was rRG1 (n 1) 100%, rRG2 (n 31) 78%, rRG3 (n 32) 62% and rRG4 (n 10) 10% (p < .0001) with a 3-year NRM of 0% - 10% - 15% - 43% respectively (p .002).ConclusionsOverall, irrespective of donor, cGvHD affects 20-50% of HCT, it is the leading cause of death in pts who survive at least 2 years without relapse, it is associated with worse quality of life and functional status. Of note, 30% of pts diagnosed with cGvHD 5 year later are still on treatment and 30% have relapse or died. Considering this context, the refined CIBMTR risk score provides a valid support in the prognostic stratification of pts at onset of cGvHD also after haplo-HCT. [Display omitted] DisclosuresMarktel:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding.

A Phase I/II Study of Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

A Phase I/II Study of Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Isolated Extramedullary (EMD) Blastic Transformation of Chronic Myeloid Leukemia (CML-BP) in the TKI Era: Characteristics, Treatments and Outcomes

Isolated Extramedullary (EMD) Blastic Transformation of Chronic Myeloid Leukemia (CML-BP) in the TKI Era: Characteristics, Treatments and Outcomes

ENDOSCOPIC VS COMBINED MEDICAL AND SURGICAL MODALITIES OF TREATMENT OF RADIATION INDUCED PROCTOCOLITIS – OUR INSTITUTE EXPERIENCE

Background: GIGastrointestinal injury may occur following irradiation of thoracic,abdominal,and pelvic malignancies limiting radiation doses that can be delivered as well as causing significant morbidity requiring intervention. Radiation proctocolitis, both acute and chronic, is one such complication requiring multidisciplinary management for good outcomes.We analyzed the injury with respect to spectrum of injury, severity, morbidity and compared endoscopic vs combined medical and surgical modalities of treatment. Methods: Patients with acute and chronic radiation proctocolitis defined as illness presenting before and after 3 months respectively,of radiation treatment were included in the study.The study period was five years. Results: Total number of patients studied were 75.Acute disease was seen in 5 patients,presenting predominantly with diarrhea, abdominal pain and acute intestinal pseudo-obstruction. Chronic radiation proctocolitis was seen in 70 patients. Bleeding per rectum was the most common symptom. Anemia was the commonest sign. Grade 2 injury was most commonly seen. Pharmacotherapy was equally effective in grade 1 injury whereas Endoscopic treatment was superior to pharmacotherapy in Grade 2,3. Surgery offered lesser rates of rehospitalization in grade 3 but was associated with higher complications. There were no deaths in endoscopic arm while there were 2 deaths in pts who required surgery. Surgical combined with medical was superior to endoscopic treatment in grade 4 while local agents were ineffective.Preventive strategies prior to radiation were associated with lower grade of injury. Conclusion: Radiation proctocolitis causes significant morbidity requiring prolonged treatment and hospitalization. Dose and duration of radiation had direct relation to the severity of injury. Concurrent chemotherapy had no effect on severity of injury.Our study showed acute proctocolitis required predominantly supportive medical treatment.Chronic form from grade 1 to 3 required predominantly endoscopic treatment with prolonged duration of treatment but less morbidity.Grade 4 required surgical and intensive care and local therapy was ineffective.

Association between post-treatment (tx) alpha-fetoprotein (AFP) reduction and outcomes in real-world (rw) U.S. patients (pts) with advanced HCC (aHCC).

341 Background: A decrease in post-tx AFP may be associated with improved outcomes in clinical trials. However, the impact of AFP reduction after initiation of a first-line (1L) tyrosine kinase inhibitor (TKI) therapy on outcomes is unclear among pts with aHCC treated in routine clinical practice. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with aHCC with ≥2 visits between 1/1/2011-7/31/2019 who received 1L TKI. Pts with a baseline serum AFP value (closest to 1L initiation within -30 to +7 days) and a post-tx AFP value (closest to 8 weeks after 1L initiation within ±2 weeks) were included. Post-tx AFP reduction was defined as a ≥20% decrease from baseline AFP, and no reduction as a &lt;20% decrease or any increase. Rw overall survival (rwOS) was defined as time from post-tx AFP measurement to death (censored at last EHR activity). Rw progression-free survival (rwPFS) was based on clinician documentation and defined as the first progression event or death after post-tx AFP measurement (censored at last clinic note date). Adjusted hazard ratios (aHR) for reduction vs no reduction (reference) were estimated using multivariable Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification was assessed by conducting tests for interactions with analyses stratified by HCC risk factors. Results: 441 pts were included in the study. 8% had documented history (hx) of hepatitis B (HBV), 52% hepatitis C (HCV), 47% obesity/diabetes (DM), 42% heavy alcohol use, and 11% no documented risk factor. Median baseline AFP was 210 ng/mL (IQR 237 - 2981) and 150 ng/mL (IQR 17 - 1311) among pts with reduction (N = 150) and no reduction (N = 291). There was a 35% decrease in hazard of death for pts with reduction vs no reduction (median rwOS 10.3 vs 6.7 months; Table). Similarly, a 35% decrease in hazard of rw progression or death was observed for pts with reduction vs no reduction (aHR=0.65; 95% CI: 0.52-0.81; median rwPFS 4.4 vs 2.4 months). Reduction (vs no) was associated with better rwOS among pts with hx of HCV, obesity/DM or alcohol use vs without the respective risk factor, however, no statistically significant interactions were observed (Table). Conclusions: Results show post-tx AFP reduction may be prognostic for rwPFS and rwOS in pts with aHCC treated with 1L TKI. Further research may clarify if prognostic value differs by HCC risk factor profile. [Table: see text]