Platinum-based Chemotherapy In Patients Research Articles

Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma

Background and AimsBiliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown. MethodTissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay. Results72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652). ConclusionBRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves’ trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

GCT-10. Successful Salvage of Relapsed intracranial Non-Germinaoteous Germ Cell Tumors NGGCTs in a Child With Renal Insufficiency with Novel platinum-Free chemotherapy Regimen

The Outcome for relapsed NGGCT is poor. Salvage therapy usually consist of reinduction platinum-based chemotherapy regimen followed by high-dose-chemotherapy and autologous-stem-cell-rescue (HDC/AuSCR) and re-irradiation with no consensus on optimal management and usually associated with remarkable toxicity. We present a 12-year-old boy diagnosed with a localized pineal Non-Germinaoteous Germ Cell Tumors NGGCTs of mixed origin with elevated AFP he had ETV and biopsy started on COG ACNS0122 protocol after receiving first cycle (carbo/Etoposide) he developed acute renal failure investigation showed small dysplastic kidney to avoid nephrotoxicity of platinum agents chemotherapy changed to VBE (Vinblastine, Bleomycin and Etoposide) post 3rd cycle MRI showed increase in size of the pineal mass with normal tumor markers representing Growing Teratoma Syndrome He had total surgical resection of the tumor Pathology showed predominant teratoma component He received radiation therapy CSI then another 3 cycles of VBE 4 months following treatment completion he presented with elevated AFB and new right anterior temporal lesion Spinal MRI and CSF were negative. He had 2 cycles of Salvage Non-nephrotoxic 4-drug regimens GEMPIV Gemcitabine 800 mg/m2 days 1 and 14. Paclitaxel 80 mg/m2 days 1 and14, Irinotecan 50 mg/m2 daily for 5 days Vinblastine 6 mg/m2 weekly days 1,8,14 MRI after 2 cycles showed remission with undetectable AFP then 2 consolidation cycles of etoposide and thiotepa (HDC/AuSCR) The 3rd consolidation cycles were cancelled due to hematological toxicity During treatment phases chemotherapy was well tolerated doses were adjusted according to his GFR with renal conservative and supportive therapy.post (HDC/AuSCR) he experienced delayed hematological recovery with persistent thrombocytopenia responded to Eltrombopag then he had focal Temporal lobe irradiation Currently patients in remission with chronic stage 3 renal Insufficiency Conclusions: this case showed that relapsed intracranial NGGCT can be successfully salvaged without platinum-based chemotherapy in patients with renal insufficiency.

Literature on target therapy of malignant melanoma.

e21506 Background: Malignant melanoma (MM) of mucosal membranes (excluding anus and head and neck) is a rare but aggressive disease with poor outcome. There is little information available on the mechanism of development, risk factors and management of this tumor, mainly due to the low number of cases. Methods: We performed a literature review on MMM (between 1970-2020) with a focus on nonsurgical management and outcome. Results: We identified 9-papers discussing 1500-MM cases. Formerly, for the management of MMM, Dacarbazine, Interferon b, DAV-Feron, Carboplatin, Imatinib, and Paclitaxel were administered. More recently, novel immunotherapeutic and chemotherapeutic medications such as Immune Checkpoint Inhibitors (ICPI) and anti-VEGF agents have been administered in these patients. In 502 patients of metastatic MMM, adding ipilimumab to dacarbazine increased OS from 9.1-to-11.2 months with one year survival increasing from 36.3%-to-47.3 %. For nivolumab & ipilimumab combination therapy in 361 patients with MMM and CMM, MPSF in nivolumab monotherapy was 3-months and 6.2-months (for MMM and CMM, respectively); but in nivo-ipili combination, MPFS was 5.9-months and 11.7-months (for MMM and CMM, respectively). A benefit of bevacizumab addition to platinum-based chemotherapy in patients showing advanced disease on ICPI is unknown; however, combination-therapy may be reasonable if no access to ICPI or autoimmune diseases. Conclusions: MMM patients could benefit from combination of nivolumab to ipilimumab more than monotherapy with either medication alone.[Table: see text]

Bevacizumab combined with platinum-based chemotherapy in patients with primary or relapsed ovarian cancer: Meta-analysis and literature review.

5582 Background: Epithelial ovarian cancer has the highest mortality rates among all gynecological malignancies and is the fifth leading cause of cancer-related deaths in females. Previously, the treatment of ovarian cancers included cytoreductive surgery in combination with platinum-based chemotherapy. While this treatment regimen initially resulted in a good response, most of the patients subsequently relapsed. Given the role of Vascular Endothelial Growth factor (VEGF) and angiogenesis in the progression of ovarian cancer, VEGF inhibitors such as Bevacizumab were considered in the treatment of advanced or relapsed ovarian cancer patients. We conducted a meta-analysis to compare the efficacy of Bevacizumab with platinum-based chemotherapy to platinum-based chemotherapy. Methods: A thorough systematic literature review identified five eligible studies reporting the efficacy of bevacizumab with platinum-based chemotherapy in the treatment of advanced or recurrent Ovarian cancer as compared to control group receiving platinum-based chemotherapy alone. These studies were randomized Phase III clinical trials, one of which was recently published in 2021. Summary estimates of the clinical endpoints were calculated with risk ratio (RR) and 95% confidence intervals using the random-effects model. Heterogeneity between studies was examined with COCHRAN’S Q based 12 statistics. The primary endpoint was progression free survival at 12 months while secondary endpoints were overall survival and certain adverse effects. Results: Our pooled analysis from the five studies included 4,648 patients. 2,641 were in the Bevacizumab and platinum-based treatment group while 2007 patients in sole-platinum based chemotherapy group. There was a statistically significant difference in primary outcome of progression free survival at 12 months was noted (RR = 1.56 (95% CI: 1.09 to 2.24; p = 0.020). 33,4% of patients in the treatment group as compared to 22.9% observed in the control group attained PFS at 12 months. The secondary outcome of overall survival at 12 months was seen in 76.7% patients in treatment group as compared to 73.02% observed in control group. This was no statistically significant difference in this case (RR = 1.04 (95% CI: 0.96 to 1.12; p = 0.34). Adverse effects including hypertension, proteinuria, arterial and venous thromboembolism, posterior reversible leukoencephalopathy syndrome occurred more frequently in the treatment group. Conclusions: Results from our meta-analysis support the superiority of Bevacizumab with platinum-based chemotherapy over platinum-based chemotherapy with regards to PFS. However, the OS benefit remains questionable.

A phase 1/2 study of the highly selective EGFR inhibitor, BLU-701, in patients with EGFR-mutant non–small cell lung cancer (NSCLC).

TPS9142 Background: Although 3rd-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, are highly effective in front-line metastatic EGFR-mutated ( EGFRm) NSCLC, treatment resistance ultimately occurs, including the emergence of the on-target C797X mutation for which there are no approved TKIs. BLU-701 is an investigational, reversible, brain-penetrant, wildtype-sparing oral TKI with nanomolar potency on common activating (exon 19 deletion and L858R) and C797X resistance mutations (Tavera L et al. AACR 2022). BLU-701 has shown promising preclinical data, including antitumor central nervous system (CNS) activity that may improve patient outcomes. Additionally, combining BLU-701 with standard of care therapies may provide enhanced disease control across multiple lines of treatment, including against heterogenous tumors, in patients with EGFRm NSCLC. Methods: HARMONY (NCT05153408) is an ongoing, global phase 1/2, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BLU-701 as a monotherapy or in combination with osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC. Key inclusion criteria include patients ≥18 years of age with metastatic EGFRm NSCLC; Eastern Cooperative Oncology Group performance status 0–1; and previous treatment with ≥1 EGFR-targeted TKI. Patients in the phase 2 monotherapy part must harbor an EGFR C797X resistance mutation (locally assessed). Key exclusion criteria are tumors harboring EGFR T790M mutations, EGFR exon 20 insertions, or other known driver alterations, including KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include ORR (phase 1), duration of response, and PK/PD (phase 1 and phase 2); disease control rate, progression-free survival, overall survival, antitumor CNS activity, and safety (phase 2). The phase 1 dose escalation will adopt a Bayesian optimal interval design. Patients will be enrolled into 3 treatment cohorts: part 1A (n≈40–80; BLU-701), part 1B (n≈35; BLU-701 + osimertinib), and part 1C (n≈18; BLU-701 + carboplatin and pemetrexed). Patients in the phase 2 dose expansion (n≈24) will be treated at the RP2D of BLU-701 as monotherapy. Patients may receive treatment until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment in this study has started, and sites will be open across North America, Europe, and Asia. Clinical trial information: NCT05153408.

SO-3 Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma

Biliary tract cancers (BTCs) are rare malignancies with a poor prognosis and scarce therapeutic strategies. The BRCAness phenotype has been shown to correlated with a good response to platinum-based chemotherapy and PARP inhibitors in several oncologic setting, but its significance in BTC is already unknown. Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATION Cdx technology. The BRCAness mutated group was defined if present at least one mutation in: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, and RTEL1, ARID1A, ATR, ATRX, CHEK1, RAD51L1, or RAD51L3. The analysis aimed to examine the association between the BRCAness phenotype and survival outcomes in patients with advanced or unresectable BTC receiving platinum-based chemotherapy. OS was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. 150 patients have been included in the analysis, 72/150 (48%) were BRCAness mutated and 78/150 (52.0%) were BRCAness wild type (WT). The most common mutated genes in the entire population were CDKN2A (31%), ARID1A (21%), CDKN2B (21%), KRAS/NRAS (19%), BAP1 (17%), PBRM1 (15%) and TP53 (11%). The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N=32, 44%), CDKN2A (N=23, 32%), KRAS/NRAS (N=16, 22%), CDKN2B (N=13, 18%), BRCA2 (N=13, 18%), PBRM1 (N=12, 17%), ATM (N=11, 15%), FGFR2 (N=10, 14%), TP53 (N=8, 11%), IRS2 (N=7, 10%), CREBBP (N=7, 10%). At the univariate analysis for PFS BRCAness mutation was associated with longer mPFS (HR 0.68; 95% CI 0.49-0.95; p=0.0254). At the univariate analysis for OS BRCAness mutation was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p=0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p=0.04) compared to patients without BRCAness mutation. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p=0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p=0.3652). ATM mutation was detected to be statistically significantly associated to a worse PFS in the BRCAness mutated population (HR 2.83; CI 95%: 1.14-7.05; p=0.0256). BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves’ trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi after response to platinum.

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial cancer (mUC) (Alliance A032001).

TPS4607 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Support: U10CA180821, U10CA180882, U24CA196171,U10CA180863 (CCTG); Clinical trial information: NCT05092958.

Timing is everything: The importance of patient-reported outcome assessment frequency when characterizing symptomatic adverse events.

Although patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial. We examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome-common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks). Similar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome-common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome-common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment. This analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.

Androgen Receptor Expression Is a Predictor of Poor Outcome in Urothelial Carcinoma

BackgroundSeveral preclinical and clinical studies demonstrated a strong correlation between androgen receptor (AR) signaling and bladder tumorigenesis. This study aims to evaluate the prognostic significance of AR expression in metastatic urothelial carcinoma (mUC).MethodsSamples from a phase III trial (LaMB, NCT00949455) which compared maintenance lapatinib versus placebo after completion of first-line platinum-based chemotherapy in patients with HER 1/2-positive mUC of the bladder were collected. Corresponding baseline and follow-up data included patients enrolled in the study and those who screen failed. AR expression was assessed independently by a single pathologist who was blinded to the study. Samples were grouped according to AR expression (negative vs. positive) and correlated with baseline tumor characteristics and survival.ResultsOf the 446 screened samples in the LaMB study, 90 were retrospectively analyzed for AR expression. There were no correlations between AR expression and tumor stage (r = −0.10), tumor grade (r = 0.05) at diagnosis, or subsequent treatment with lapatinib (r = −0.04). The median progression-free survival was 6 months (95% CI, 3.20–6.80) in the AR-negative group and 5 months (95% CI, 3.41–6.59) in the AR-positive group [HR 0.54 (95% CI, 0.31–0.92), p = 0.02]. Similarly, patients with AR-negative disease had more favorable overall survival (OS) with 16 months (95% CI, 6.6–25.4) and 11 months (95% CI, 7.0–15.0) in the AR-positive group [HR 0.55 (95% CI, 0.31–0.98), p = 0.04]. In the multivariate analysis, AR expression was significantly associated with worse OS (p = 0.045).ConclusionsAR expression is a predictor of poor outcome and presents a targetable alteration in patients with mUC.

Feasibility of Tumor Treating Fields with Pemetrexed and Platinum-Based Chemotherapy for Unresectable Malignant Pleural Mesothelioma: Single-Center, Real-World Data.

Simple SummaryManagement of malignant pleural mesothelioma (MPM) is challenging as patients frequently present with unresectable disease and the response rates with systemic therapy alone remain low. Given the paucity of effective therapies for MPM, Tumor Treating Fields (TTFields) therapy was made available for use under an FDA-approved Humanitarian Device Exemption (HDE) protocol in 2019, but no real-world data beyond the initial trial have been published to date. We reviewed our retrospective series of five patients diagnosed with MPM and treated with TTFields with pemetrexed and platinum-based chemotherapy. This therapy resulted in a modest disease-stabilization rate with no significant device-related major toxicities. However, we observed universal low-grade skin toxicities related to the device which required medical management and self-discontinuation in 2/5 patients. We also observed lower device usage, compared to the STELLAR trial. Both of these represent opportunities for developing improved management guidelines and efforts to improve patient compliance. Purpose: The objectives of this study were to evaluate the implementation, device usage rates, clinical outcomes, and treatment-related toxicities associated with TTFields and pemetrexed plus platinum-based chemotherapy in patients with unresectable MPM, outside the initial trial results. Methods: Consecutive patients with unresectable MPM were enrolled onto an FDA-required HDE protocol from 2019 to 2021. All patients were treated with a protocol-defined regimen of continuous TTFields (150 kHz) and pemetrexed plus platinum-based chemotherapy. Results: Five patients with unresectable MPM were enrolled. The median number of 4-week TTFields cycles was 5 (range: 2–7 cycles). Median TTFields device usage in the first 3 months was 12.5 h per day (range: 5–16.8 h), representing 52% (21–70%) of the potential daily duration. The median follow-up was 5.4 months (range: 1.1–20.9 months). Treatment-related dermatitis was the only side effect associated with TTFields and was reported as grade 1–2 in all patients; no patient had grade 3+ device-related toxicities. Conclusions: This study represents the first results of real-world implementation of TTFields for MPM. In comparison to the initial clinical trial (STELLAR), compliance rates were lower, although skin-related toxicities appeared similar. Further initiatives and guidelines should be developed to manage treatment-related dermatitis and improve device usage.

Olaparib beyond progression compared with platinum chemotherapy after secondary cytoreductive surgery in patients with recurrent ovarian cancer: phase III randomized, open-label MITO 35b study, a project of the MITO-MANGO groups

BackgroundPoly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an...

Prediction of platinum-based chemotherapy sensitivity for epithelial ovarian cancer by multi-sequence MRI-based radiomic nomogram

Objective: To investigate a preoperative multi-sequence MRI-based radiomic nomogram for prediction of platinum-based chemotherapy sensitivity in patients with epithelial ovarian cancer (EOC). Methods: The complete data of 114 patients with EOC confirmed by surgery and pathology in Nantong Tumor Hospital of Nantong University from January 2015 to May 2020 were retrospectively analyzed, with an average age of 32-76 (57±8) years. All patients underwent platinum-based chemotherapy after maximal cytoreductive surgery. According to whether relapse occurred within 6 months, those patients were divided into platinum-resistant disease (PR, n=39) group and platinum-sensitive disease group (PS, n=75).All patients underwent MRI examination before treatment, and the 3-dimensional solid component of the tumor area of interest (ROI) on T2-weighted image (T2WI), diffusion weighted imaging (DWI) and T1-weighted image-enhanced image (T1CE) were manually delineated using Itk-snap software.Then AK software was imported for radiomics features extracting. They were randomly divided into training group (n=80) and validation group (n=34) in a ratio of 7∶3 (stratified sampling method). Firstly, the radiomics features were initially screened by the method of maximum correlation and minimum redundancy (mRMR), and features with the greatest predictive power were retained. Then, the LASSO regression analysis was performed to select the best features and construct the radiomics model. Univariate analysis was used to screen out clinical relevant factors, which combined with radiomic score (Radscore) was applied to develop a radiomics nomogram by multivariable logistic regression. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate the predictive ability and clinical application value of radiomics model, clinical related factor model and radiomics nomogram. Results: Compared with the radiomics model (12 optimal radiomics features) and the clinical relevant factors model (residual disease, neutrophil count, carbohydrate antigen 199), the radiomics nomogram model demonstrated the best prediction performance: in the training groups, the AUC (Area Under the ROC Curve), accuracy, sensitivity, and specificity were 0.90 (95%CI:0.82-0.99), 90.0%, 89.0%, and 92.0%, respectively. In the validation groups, the AUC, accuracy, sensitivity, and specificity were 0.89 (95%CI:0.78-1.00), 85.0%, 87.0%, and 80.0%, respectively. DCA shows that the use of nomograms with a threshold in the range of 0.01 to 0.90 has a greater clinical application value in predicting the sensitivity of platinum chemotherapy in patients with EOC. Conclusion: The multi-sequence MRI-based radiomics nomogram has a high diagnostic value in predicting the sensitivity of platinum-based chemotherapy in patients with EOC.

Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37–1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43–1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23–3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31–9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08–4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27–3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44–3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.

POSA243 Approaches to Immune Checkpoint Inhibitor (ICI) First-Line Maintenance Therapy (1L-MT) in Unresectable Locally Advanced (LA) or Metastatic Urothelial Cancer (mUC) in France, Germany, Italy, Spain, and the UK (EU5)

Avelumab was approved for 1L-MT following disease control with platinum-based chemotherapy in patients with LA/mUC in the EU (January 2021). This survey aimed to understand how EU physicians might incorporate this novel treatment approach into clinical practice.

Real-World Outcome of Platinum-Based Chemotherapy in Advanced Breast Cancer (ABC): A Retrospective Study from a Tertiary Cancer Center in India

Abstract Introduction There is a paucity of data on platinum-based chemotherapy in advanced breast cancer (ABC) from developing countries like India. Objectives The objectives were to analyze the efficacy and safety of platinum-based chemotherapy in patients with ABC. Materials and Methods This was a retrospective study of 35 patients with ABC who were treated with platinum-based chemotherapy (gemcitabine and carboplatin, [GC]) in a tertiary cancer center in India from August 2015 to November 2019. The inclusion criteria were patients with ABC, who had received palliative chemotherapy with GC. The exclusion criteria were patients who had received less than two cycles of GC and patients who received platinum-based chemotherapy for neuroendocrine carcinoma of the breast. Results The median age was 45 years (range: 28–68 years). All patients were female (97%) except one male (3%). The histology was ductal carcinoma (77%), mixed (17%), and others (6%). Out of the 12 patients tested for breast cancer (BRCA) gene mutation, six patients had a BRCA mutation. Patients with metastatic and locally progressive disease were 91 and 9%, respectively. The median number of prior lines of systemic therapy for metastatic disease was 1 (range: 0–5). The median number of sites of metastasis was 2 (range: 0–5). Patients with visceral crises were 23%. The median number of cycles of GC chemotherapy received was 6 (range: 2–6). A dose reduction in chemotherapy was done in 74%. The responses among 34 evaluable patients were complete response (11%), partial response (24%), stable disease (41%), and progressive disease (24%). Grade 3 or more hematological and nonhematological toxicities were observed in 69 and 9%, respectively. The median progression-free survival and overall survival were 6 and 8 months, respectively. The 1-year progression-free survival and overall survival were 19 and 34%, respectively. Multivariate analysis showed that patients who had received more than 3 cycles had a better outcome. Conclusion GC was an active and well-tolerated regimen in ABC regardless of the receptor status. Further prospective randomized studies are warranted to assess the optimal regimen in patients with triple-negative breast cancer.

150P Subgroup analysis of ORIENT12: Efficacy of sintilimab in combination with gemcitabine and platinum-based chemotherapy in patients with advanced or metastatic squamous non-small cell lung cancer

Sintilimab in combination with gemcitabine and platinum-based chemotherapy has shown good efficacy in a randomized, double-blind, phase 3 study in Chinese patients with squamous NSCLC (ORIENT 12). This subgroup analysis assessed the efficacy of sintilimab combination stratified by key baseline patient characteristics (PD-L1 expression level and disease staging).

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

ERCC1 19007 Polymorphism in Greek Patients with Advanced Urothelial Cancer Treated with Platinum-Based Chemotherapy: Effect of the Changing Treatment Paradigm: A Cohort Study by the Hellenic GU Cancer Group.

We previously showed that ERCC1 19007 C>T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease.

Phase II Study of Nivolumab Plus Ipilimumab with Platinum-Based Chemotherapy for Treatment-Naïve Advanced Non-Small Cell Lung Cancer with Untreated Brain Metastases: NIke Trial (LOGiK2004).

The standard of care for advanced non-small cell lung cancer (NSCLC) without known driver oncogenes is immune checkpoint inhibitor (ICI) therapy combined with platinum-based chemotherapy. About 20% of patients with advanced NSCLC have brain metastases, which are related to poor prognosis. However, the effect of ICI therapy combined with platinum-based chemotherapy on untreated brain metastases derived from NSCLC remains unclear. The primary endpoint of this study is intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥5 mm as target lesions. Eligible patients are 20 years of age or older with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive nivolumab plus ipilimumab intravenously combined with histology-based platinum doublet chemotherapy (two cycles). Individuals with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Planned enrollment is 30 patients over 2.5 years at 27 oncology facilities in Japan. This is the first prospective study to focus on the intracranial response to ICI therapy combined with platinum-based chemotherapy in patients with untreated brain metastases derived from NSCLC. If the study demonstrates intracranial efficacy for this patient population, then this regimen has the potential to become a new treatment option for such individuals.

P14.06 Toripalimab in Combination With Bevacizumab and Platinum-Based Chemotherapy in Patients with Untreated Advanced PSC: A Phase II Study

Although immunotherapy has emerged as a standard treatment for advanced non-small cell lung cancer (NSCLC) without driver gene mutation, there are still insufficient data on the efficacy of immunotherapy for patients with pulmonary sarcomatoid carcinoma (PSC). Due to a high tumor mutation burden and great prevalence of programmed cell death ligand 1 (PD-L1) in PSC than other subtypes of NSCLC, immunotherapy may provide promising efficacy in advanced PSC patients. Multiple immune-monotherapy or combination with chemotherapy case studies and doublet immunotherapy based on a phase II study (NCT03022500) suggested the survival benefit of immunotherapy in advanced PSC. Blood-vessel invasion as an independent factor associated with PD-L1 expression and poor prognosis in PSC, early application of anti-angiogenesis may enhance patients' response to immunotherapy. The application of anti-programmed cell death protein 1 (PD-1) antibody combined with platinum-based chemotherapy plus anti-angiogenesis in untreated advanced PSC is worth exploring. Toripalimab, a humanized IgG4 monoclonal antibody against PD-1, achieved partial response (PR) for second-line advanced PSC in a recent case report (Jiao Y Oral Oncology 2020). Based on these pieces of evidence, we explore the combination of toripalimab with platinum-based chemotherapy and bevacizumab in patients with untreated advanced PSC. This is an open-label, multicenter, single-arm, phase II study that aims to evaluate the efficacy and safety of toripalimab combination with platinum-based chemotherapy and bevacizumab in patients with untreated advanced PSC. Key eligibility criteria include age 18-75 years with Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed PSC, at least 1 measurable lesion per RECIST v1.1 that not received radiotherapy, and no prior anti-PD-1 or anti-PD-L1 therapy for stage IV PSC. Patients will be excluded if they have evidence of mutations in either EGFR, ROS-1, ALK, or c-MET. 27 untreated advanced PSC patients at 5 sites will be enrolled in Chengdu city, Sichuan province of China. All patients will receive toripalimab (240 mg, d1) combined with bevacizumab (7.5 mg/kg, d1) and nab-paclitaxel (260 mg/m2, d1 or 130 mg/m2, d1,8) plus carboplatin (AUC= 4-5, d1) of a 21-day cycle for a maximum of 6 cycles. Patients will continue to receive maintenance therapy with toripalimab and bevacizumab until disease progression or died of two years. The primary endpoint is progression-free survival (PFS) by investigator assessment per RECIST v1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), the patient-reported outcome (PRO), and safety data per NCI-CTC AE 4.0.3. Enrollment for this trial is open in April of this year and will continue for 12 months. Not applicable. Not applicable.