First-line Platinum Research Articles

Real-World Treatment Patterns, Survival, and Costs for Ovarian Cancer in Canada: A Retrospective Cohort Study Using Provincial Administrative Data.

Background: In 2020, approximately 3100 Canadian women were diagnosed with ovarian cancer (OC), with 1950 women dying of this disease. Prognosis for OC remains poor, with 70% to 75% of cases diagnosed at an advanced stage and an overall 5-year survival of 46%. Current standard of care in Canada involves a combination of cytoreductive surgery and platinum-based chemotherapy.Objective: There are few studies reporting current OC costs. This study sought to determine patient characteristics and costs to the health system for OC in Ontario, Canada.Methods: Women diagnosed with OC in Ontario between 2010 and 2017 were identified. The cohort was linked to provincial administrative databases to capture treatment patterns, survival, and costs. Overall total and mean cost per patient (unadjusted) were reported in 2017 Canadian dollars, using a macro-based costing methodology called GETCOST. It is programmed to determine the costs of short-term and long-term episodes of health-care resources utilized.Results: Of the 2539 OC patients included in the study, the mean age at diagnosis was 60.4±11.35 years. The majority were diagnosed with stage III disease (n=1247). The only treatment required for 74% of stage I patients and 54% of stage II patients was first-line (1L) platinum chemotherapy; in advanced stages (III/IV) 24% and 20%, respectively, did not receive further treatment after 1L therapy. The median overall survival (mOS) for the whole cohort was 5.13 years. Survival was highest in earlier stage disease (mOS not reached in stage I/II), and dropped significantly in advanced stage patients (stage III: mOS=4.09 years; stage IV: mOS=3.47 years). Overall mean costs in patients stage I were CAD $58 099 compared to CAD $124 202 in stage IV.Discussion: The majority of OC patients continue to be diagnosed with advanced disease, which is associated with poor survival and increased treatment costs. Increased awareness and screening could facilitate diagnosis of earlier stage disease and reduce high downstream costs for advanced disease.Conclusion: Advanced OC is associated with poor survival and increased costs, mainly driven by hospitalizations or cancer clinic visits. The introduction of new targeted therapies such as olaparib could impact health system costs, by offsetting higher downstream costs while also improving survival.

801P Response to first-line platinum chemotherapy in microsatellite instability high (MSI-H) metastatic endometrial carcinoma

Between 17 to 25% of recurrent or metastatic endometrial carcinoma (EC) are MSI-H which results in improved response to immune checkpoint inhibitors (ICI). However, little is known regarding chemotherapy sensitivity in MSI-H EC, especially response to first-line platinum-based treatment.

Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease.

Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC). Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS). One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p=.035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p=.041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases. After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC. Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.

Predicting response to platinum and non-platinum drugs through bioluminescence resonance energy transfer (BRET) based bio-molecular interactions in platinum resistant epithelial ovarian cancer

Therapy induced rewiring of signalling networks often lead to acquirement of platinum-resistance, thereby necessitating the use of non-platinum agents as second-line treatment particularly for epithelial ovarian cancer (EOC). A prior subject-specific assessment can guide the choice of optimal non-platinum agent/s and possible targeted therapeutic/s. Assessment of protein-protein interactions are superior to simple cytotoxicity assays to determine therapeutic efficacy and associated molecular responses. Utilizing improved PIP3-AKT and ERK1/2 activation Bioluminescence Resonance Energy Transfer (BRET) sensors, we report chemotherapy-induced ERK1/2 activation predominantly in cisplatin-paclitaxel resistant EOC cells and increased activation of both ERK1/2 and AKT in malignant ascites derived cancer cells from platinum-resistant patients but not from treatment-naive or platinum-sensitive relapse patients. Further, majority of the non-platinum drugs except irinotecan increased ERK1/2 activation in platinum-taxol resistant cells as observed by live-cell BRET assessment which were associated with p90RSK1/2 and BAD activation along with upregulation of multidrug transporter gene ABCC1 and cell survival genes like cyclin D1 and Bcl2. Interestingly, only irinotecan was able to sensitize these resistant cells. Altogether, this first report of BRET based sensing of molecular pathway activations in platinum resistant cell lines and patient's derived cancer cells highlight the clinical potential of BRET sensors in management of therapy resistant cancer.

Genitourinary (Non-Prostate) Cancers: 2021 ASCO Annual Meeting Highlights for the Advanced Practitioner.

Following coverage from The ASCO Post, Emily Lemke, DNP, AGPCNP-BC, AOCNP®, of Medical College of Wisconsin Cancer Center, comments on an adjuvant trial of a checkpoint inhibitor for clear cell renal cell carcinoma (RCC), real-world data comparing first-line platinum regimens for patients with metastatic urothelial carcinoma, and combination regimens for RCC.

Adjuvant chemotherapy of three steps (ACTS) in patients with newly diagnosed advanced ovarian cancer: interim analysis of a randomized phase II trial

<h3>Objectives:</h3> Decades ago, we developed adjuvant chemotherapy of three steps (ACTS) in advanced ovarian cancer, of which the first step is first-line platinum–taxane chemotherapy for six cycles, the second step is cyclophosphamide-etoposide per four weeks for six cycles, the third step is cyclophosphamide-platinum per eight weeks for six cycles. Here, we aimed investigate the efficacy and safety of ACTS in advanced ovarian cancer by randomized controlled trial. <h3>Methods:</h3> We conducted a randomized, open-label, controlled single center phase 2 trial. Eligible patients had newly diagnosed, advanced (FIGO2014 stage IIIc/IV), high-grade ovarian cancer and were having a complete response after optimal cytoreductory surgery and first-line platinum–taxane chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive step 2 and 3 of ACTS (ACTS group, step 2: cyclophosphamide 0.4g d1-d3 IV + etoposide 0.1g d1-d3 IV per 4 weeks for six cycles; step 3: cyclophosphamide 0.6g d1-d2 IV + carboplatin AUC=5 d1 IV per 8 weeks for 6 cycles) or no treatment (control group). The primary endpoint was overall survival, the secondary endpoints were progression-free survival and safety. <h3>Results:</h3> Of the 130 patients who underwent randomization, 65 were assgined to ACTS group. In the interim analysis, the median progression-free survival was significantly longer in the ACTS group than in the control group (22.0 months vs. 9.53 months; hazard ratio for disease progression or death, 0.559; 95% confidence interval [CI], 0.368-0.849; P=0.006, Fig.1). In the interim analysis of overall survival (performed after the deaths of 15 of 130 patients [11.8%] in the overall population), the estimated Kaplan–Meier probability of survival at 36 months was 90.7% in the ACTS group and 79.0% in the control group (hazard ratio for death, 0.42; 95% CI, 0.146 to 1.21). The most common adverse events of grade 3 or higher were neutropenia (in 62.7%), and thrombocytopenia (in 11.9%). No treatment-related deaths occurred. <h3>Conclusions:</h3> Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received adjuvant chemotherapy of three steps (ACTS) had significantly longer progression-free survival than those who didn't. (ClinicalTrials., NCT02562365.).

Comprehensive Dissection of Treatment Patterns and Outcome for Patients With Metastatic Large-Cell Neuroendocrine Lung Carcinoma.

BackgroundLarge-cell neuroendocrine lung carcinoma (LCNEC) is a rare pulmonary neoplasm with poor prognosis and limited therapeutic options.MethodsWe retrospectively analyzed all patients with metastatic LCNEC in the records of a large German academic center since 2010.Results191 patients were identified with a predominance of male (68%) smokers (92%) and a median age of 65 years. The single most important factor associated with outcome was the type of systemic treatment, with a median overall survival (OS) of 26.4 months in case of immune checkpoint inhibitor administration (n=13), 9.0 months for other patients receiving first-line platinum doublets (n=129), and 4.0 months with non-platinum chemotherapies (n=17, p<0.01). Other patient characteristics independently associated with longer OS were a lower baseline serum LDH (hazard ratio [HR] 0.54, p=0.008) and fewer initial metastatic sites (HR 0.52, p=0.006), while the platinum drug type (cisplatin vs. carboplatin) and cytotoxic partner (etoposide vs. paclitaxel), patients’ smoking status and baseline levels of tumor markers (NSE, CYFRA 21-1, CEA) did not matter. 12% (23/191) of patients forewent systemic treatment, mainly due to tumor-related clinical deterioration (n=13), while patient refusal of therapy (n=5) and severe concomitant illness (n=5) were less frequent. The attrition between successive treatment lines was approximately 50% and similar for platinum-based vs. other therapies, but higher in case of a worse initial ECOG status or higher serum LDH (p<0.05). 19% (36/191) of patients had secondary stage IV disease and showed fewer metastatic sites, better ECOG status and longer OS (median 12.6 vs. 8.7 months, p=0.030). Among the 111 deceased patients with palliative systemic treatment and complete follow-up, after exclusion of oligometastatic cases (n=8), administration of local therapies (n=63 or 57%) was associated with a longer OS (HR 0.58, p=0.008), but this association did not persist with multivariable testing.ConclusionsHighly active systemic therapies, especially immunotherapy and platinum doublets, are essential for improved outcome in LCNEC and influence OS stronger than clinical disease parameters, laboratory results and other patient characteristics. The attrition between chemotherapy lines is approximately 50%, similar to other NSCLC. Patients with secondary metastatic disease have a more favorable clinical phenotype and longer survival.

Prognostic role of pretreatment lung immune prognostic index in extensive-stage small-cell lung cancer treated with platinum plus etoposide chemotherapy.

To investigate the prognostic role of lung immune prognostic index (LIPI) in extensive-stage small-cell lung cancer (ES-SCLC) patients treated with platinum plus etoposide chemotherapy. Data were obtained from two randomized controlled trials (NCT00119613 and NCT00363415). Overall survival (OS) and progression-free survival (PFS) was assessed according to LIPI score through Kaplan-Meier analysis. Univariate and multivariate Cox-regression analysis were performed to investigate predictors for OS and PFS. A total of 911 patients with ES-SCLC treated with platinum plus etoposide chemotherapy (CT) were included for analysis. The median age at diagnosis was 62 years, and 760 (83.4%) had performance status of 1 or less. 1-year OS for ES-SCLC with poor, intermediate, and good LIPI was 20%, 30% and 31%, respectively, and 1-year PFS was 7%, 15% and 21%, respectively. Cox-regression analysis showed that the PFS and OS of ES-SCLC with a poor LIPI score was significantly worse than those with good LIPI scores (HR 1.81, 95% CI: 1.38-2.36; p< 0.001 and HR 1.35, 95% CI: 1.07-1.72, p= 0.012), while no significant difference was observed between intermediate and poor LIPI groups in terms of OS (HR 1.01, 95% CI: 0.82-1.23, p= 0.82), but not for PFS (HR 1.27, 95% CI: 1.00-1.61, p= 0.048). In addition, LIPI score was significantly associated with disease control rate and objective response rate (both p< 0.0001). Prognosis of patients with pretreatment LIPI score of 2 is poorer than those with LIPI score of 0-1 among ES-SCLC who received first-line platinum plus etoposide chemotherapy; Further studies are still recommended to confirm our findings in prospective studies.

Real-world time on treatment with immuno-oncology therapy in recurrent/metastatic head and neck squamous cell carcinoma.

Aim: We report real-world time on treatment (rwToT) with immuno-oncology (I-O)and other systemic therapies in second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) previously treated with platinum therapies. Materials & methods: Adult patients receiving first-line platinum therapy for R/M HNSCC between January 2017 andDecember 2018 and a second-line therapy were selected from a US electronic medical record database. Results: In our study sample of 619 R/M HNSCC patients, second-line treatments primarily included I-O therapies (71%) and resulted in median rwToT of 2.8months and 12-month on-treatment rate of 19.3%. For other second-line therapies, median rwToT and 12-month on-treatment rate was 1.9months and 1.3%, respectively. Conclusion: Use of second-line I-O therapies was common and resulted in rwToT consistent with R/M HNSCC clinical trials.

Real-world outcomes of second-line ramucirumab plus paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A nationwide retrospective study in Korea (KCSG-ST19-16).

4056 Background: Ramucirumab as monotherapy or in combination with paclitaxel is a second-line treatment option recommended for patients with locally advanced unresectable or metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma. However, real-world data of large samples focused on ramucirumab plus paclitaxel in gastric cancer are limited. We conducted a nationwide retrospective study to evaluate the efficacy, safety, and factors potentially associated with survival in patients with gastric or GEJ adenocarcinoma who received second-line ramucirumab plus paclitaxel in a real-world setting. Methods: The study population comprised all patients with gastric or GEJ cancer who received ramucirumab plus paclitaxel in South Korea between May 1, 2018, and December 31, 2018. We included patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum and fluoropyrimidine-containing combination chemotherapy. Results: A total of 1,063 patients with advanced gastric or GEJ adenocarcinoma who received ramucirumab plus paclitaxel were included. The objective response rate and disease control rate were 15.1% and 57.7%, respectively; the median progression-free survival was 4.03 months (95% CI, 3.80–4.27), and the median overall survival was 10.3 months (95% CI, 9.33–10.73). The common treatment-related adverse events (TRAEs) at any grade were neutropenia (44.7%), anemia (41.8%), neuropathy (29.1%), fatigue (25.9%), and anorexia (25.0%). Grade 3 or higher TRAEs with incidences of ≥5% were neutropenia (35.1%) and anemia (10.5%). Adverse events of special interest were infrequent, including hypertension (2.1%) and proteinuria (3.0%). Based on multivariate analysis, overall survival was negatively associated with Eastern Cooperative Oncology Group performance status ≥2, weight loss in the previous 3 months ≥10%, GEJ of primary tumor, poor or unknown histology grade, number of metastatic sites ≥3, presence of peritoneal metastasis, no prior gastrectomy, and time to second-line since first-line treatment &lt; 6 months. Conclusions: Our large-scale, nationwide, real-world data analysis of an unselected real-world population added evidence for the efficacy and safety of second-line ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Clinical trial information: NCT04192734.

Adoption of consolidative durvalumab among patients with locally advanced non-small cell lung cancer.

e20550 Background: Soon after the publication of the PACIFIC trial, the Food and Drug Administration (FDA) approved durvalumab following definitive chemoradiation in patients with unresectable stage III non-small cell lung cancer (NSCLC). However, patterns of durvalumab adoption within the United States are currently unknown. We investigated the pace of uptake of durvalumab as well as patient and tumor characteristics associated with receipt of durvalumab following FDA approval. Methods: This study used the nationwide Flatiron Health database, a longitudinal electronic health record-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). From this de-identified database, we selected patients with stage IIIB-C NSCLC who completed at least two cycles of first-line (1L) platinum doublet chemotherapy between February 16, 2018 (FDA approval date for durvalumab) and August 16, 2019, and did not develop disease progression over a follow-up period of at least 120 days after 1L chemotherapy. In the absence of radiation therapy and surgery details in the database, these criteria served as a proxy for selecting patients who were most likely to be eligible for consolidative durvalumab. We evaluated temporal trends in the uptake of durvalumab after completion of 1L chemotherapy using the Cochran-Armitage test, clustering the time periods in 3-month intervals. We also characterized patient and tumor characteristics associated with durvalumab receipt using the chi-square test and multivariable logistic regression. Results: A total of 424 patients were included in our study sample, among whom 282 (66.5%) patients had documentation of having received durvalumab after 1L chemotherapy. Within the first 3 months after FDA approval, 60.4% of potentially eligible patients received durvalumab, while in the final 3 months of the study period, this proportion rose modestly to 68.3% (p = 0.19). On univariable and multivariable analysis, patient characteristics like age, sex, race, insurance, smoking status, performance status, and comorbidity score, as well as tumor characteristics like histology, EGFR status, and PD-L1 status, were not significantly associated with receipt of durvalumab. However, there was significant geographic variability in receipt of durvalumab, ranging from 65.7% in the South to 85.3% in the Midwest (chi-square p = 0.04). Conclusions: Early adoption of durvalumab upon completion of 1L chemotherapy for stage IIIB-C lung cancer was rapid across the United States, starting at over 60% in the first three months after FDA approval. Regional variation appears to be a more powerful driver than patient characteristics in discrepancies of durvalumab dissemination. Further exploration into these regional variations may help improve guideline-concordant care.

Clinicopathologic, genomic, and tumor microenvironment correlates of aneuploidy and immunotherapy outcomes in NSCLC.

9119 Background: Cancer aneuploidy, an unbalanced number of chromosomes, is associated with somatic mutation rate, expression of proliferative genes, and altered immune signaling. Whether aneuploidy correlates to a distinct immunophenotype or impacts clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC is unclear. Methods: In NSCLCs which underwent targeted next-generation sequencing, we retrospectively analyzed the aneuploidy score (AS), defined as the sum of the number of altered chromosome arms. An unbiased recursive partitioning (URP) algorithm was used to investigate an AS cutoff to discriminate responders from non-responders to ICIs. Multiplexed immunofluorescence to quantify CD8+, Foxp3+, PD-1+, and PD-L1 expression was performed to determine differences in tumor immune cells subsets according to AS cutoff. Results: Among 436 NSCLCs identified, stage I tumors (median AS 1) had significantly lower median AS (mAS) than stage IV cancers (mAS 7, P &lt; 0.001), stage III (mAS 4, P = 0.03), and numerically lower compared to stage II cancers (mAS 3, P = 0.18). We found no difference in the mAS across tumors with a PD-L1 tumor proportion score of ≥50%, 1-49%, or &lt; 1% (mAS 5 vs 7 vs 6, respectively, P = 0.26), nor was there any correlation between aneuploidy and TMB when taken as continuous variables (Spearman R: 0.074, P = 0.12). A total of 279 advanced NSCLCs with available aneuploidy scores were treated with ICIs. An URP analysis identified an AS of 2 as the strongest discriminator of objective response to ICI. Compared to pts with an AS &gt; 2 (N = 207, 74.2%), pts with AS ≤2 (N = 72, 25.8%) had a significantly higher objective response rate (ORR 43.0% vs 19.8%, P &lt; 0.001), a significantly longer median progression-free survival (mPFS 6.2 vs 2.9 months, HR: 0.70 [95% CI: 0.52-0.94], P = 0.02), and a significantly longer median overall survival (mOS 19.8 vs 13.8 months, HR: 0.66 [95% CI: 0.47-0.94], P = 0.02) to treatment with ICIs. After adjusting for other variables such as performance status, presence of oncogenic driver mutation, PD-L1, TMB, and line of treatment, AS was significantly associated with improved mPFS (HR: 0.72 [95% CI: 0.52-0.99], P = 0.04) and mOS (HR: 0.64 [95% CI: 0.44-0.94], P = 0.02). By contrast, among pts who received first-line platinum doublet chemotherapy without ICI, an AS ≤2 (N = 29), when compared to an AS &gt; 2 (N = 56), did not correlate with improved ORR (55.2% vs 44.6%, P = 0.4) or PFS (5.3 vs 4.8 months, HR 0.83 [95% CI: 0.5-1.3], P = 0.43). Among 179 NSCLCs profiled by multiplex immunofluorescence, compared to cancers with an AS &gt; 2, those with low aneuploidy had significantly higher numbers of CD8+, Foxp3+, PD-1+ immune cells, and PD-1+ CD8+ T cell, both intratumorally and when looking at the total numbers of cells within the tumor and at the tumor-stroma interface. Conclusions: NSCLCs with low aneuploidy have a distinct immune microenvironment and more favorable outcomes to ICIs.

Clinical and mutational profile of ARID1A-mutated gastrointestinal cancers: Duration of response to platinum-based chemotherapy.

e15611 Background: ARID1A is mutated in several cancer types, with studies reporting mutations in up to 10% of colorectal cancers (CRC) and as high as 35% of gastric and pancreatic cancers. The ARID1A gene encodes a member of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex and functions as a tumor suppressor. ARID1A has also been implicated in double-stranded DNA repair via both homologous recombination and non-homologous end-joining, potentially conferring platinum sensitivity. We sought to characterize this subset of gastrointestinal (GI) malignancies. Methods: We identified patients with locally advanced or metastatic ARID1A-mutated GI malignancies treated at Massachusetts General Hospital (MGH) by next-generation sequencing. Patients were selected who gave consent to molecular testing and who were enrolled on to a study. We evaluated clinical characteristics and outcomes for patients undergoing treatment at MGH between 2009 and May 2020. The Kaplan-Meier method was used to calculate progression free survival (PFS) to first-line platinum-based chemotherapy. Results: We captured 38 patients with ARID1A-mutated tumors. Median age at diagnosis was 66 (range 31-87) and 63.2% of patients were male (n = 24). Tumor types varied, including CRC (n = 13, 34.2%), esophagogastric (n = 13, 34.2%), pancreatic (n = 6, 15.7%), cholangiocarcinoma (n = 2, 5.3%), small bowel (n = 1, 2.6%), anal (n = 1, 2.6%), and unknown GI primary (n = 2, 5.3%). Most were metastatic at diagnosis (n = 23, 60.5%). The identified ARID1A mutations were each distinct, occurring along the length of the gene and were comprised of missense (n = 10, 26.3%), nonsense (n = 12, 31.6%), frameshift (n = 13, 34.2%), and splice-site (n = 3, 7.9%) mutations. We observed on average 4-5 co-mutations per tumor, with TP53 (n = 25, 65.8%), KRAS (n = 14, 36.8%), APC (n = 11, 28.9%), BRCA2 (n = 7, 18.4%) and BRAF (n = 7, 18.4%) occurring most frequently. Tumors were both microsatellite stable (n = 23, 60%) and microsatellite unstable (n = 7, 18.4%). Most patients (n = 37, 97.4%) received a platinum-based chemotherapy as first-line therapy including FOLFOX (n = 23, 60.5%), FOLFIRINOX (n = 10, 26.3%), gemcitabine/cisplatin (n = 2, 5.3%), carboplatin/5-FU (n = 1, 2.6%), and carboplatin/etoposide (n = 1, 2.6%). Median PFS for first-line platinum based chemotherapy was 14.0 months (CI 8.2-34.7) overall. For patients with CRC, PFS to platinum-based therapy was 14.0 months (CI 4.8-not reached) compared with 9.6 months for non-CRC (CI 7.4-not reached). Conclusions: To our knowledge, this is the first assessment of clinical characteristics and outcomes for ARID1A-mutated GI malignancies. Mutations in ARID1A are highly diverse, without a clear association with tumor type. Future studies assessing response to platinum-based chemotherapy are warranted.

Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who receive second-line immunotherapy.

4535 Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cisplatin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Carbo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69-1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted.[Table: see text]

Inhibition of ALDH1A1 Activity in Cisplatin-Resistant Ovarian Cancer Cells Alters Their Cancer Stemness, Cell Cycle Profile and Mitochondrial Respiration Rate

Introduction: Ovarian cancer is one of the leading cause of morbidity and death among women, with a five-year relative survival rate of only 30% in patients diagnosed with distant metastasis. The ovarian cancer cells initially respond to first-line platinum drug cisplatin [cis-diamminedichloroplatinum(II) (CDDP)] treatment. But, they subsequently develop resistance to CDDP and eventually exhibit chemoresistance. Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is one of the key functional markers of ovarian cancer stem cells (CSCs) that confers cancer stemness and therapeutic resistance, and is associated with poor prognosis and patient survival. In this study, we have assessed the anticancer effects of the ALDH1A1 inhibitor, A37, in CDDP-resistant ovarian cancer cells in vitro. Experimental Methods: SK-OV-3-CDDP, cisplatin-resistant ovarian cancer cells were treated with different concentrations of the small molecule inhibitor of ALDH1A1, A37. We determined the cell proliferation using water-soluble tetrazolium salt (WST-1) assay at 24 and 48 h. The distribution of cell division phases by cell cycle analysis and oxygen consumption rate (OCR) via seahorse extracellular flux analysis were assessed by flow cytometry and seahorse XFe24 analyzer, respectively. Furthermore, we examined the protein expression of key signaling molecules by western blot analysis and cancer stemness by tumorsphere formation assay. Results: Treatment of SK-OV-3-CDDP cells with A37 significantly reduced the ovarian cancer cell proliferation. Interestingly, A37 induced cell cycle arrest as observed by an increase in G1 phase of the cell cycle. Additionally, A37 reduced the mitochondrial respiration of ovarian cancer cells as observed by the decrease in basal OCR. Moreover, A37 treatment markedly decreased the expression of WW domain containing transcription regulator 1 (WWTR1) protein [also called as transcriptional co-activator with PDZ-binding motif (TAZ)], which is a key downstream effector of mammalian Hippo signaling pathway that promotes cancer stemness, metastasis and chemoresistance. Importantly, A37 reduced the number and size of the tumorspheres. Conclusions: Our study suggests that inhibiting the ALDH1A1 activity using A37 reduced the cell proliferation and induced cell cycle arrest in CDPP-resistant ovarian cancer cells. The mechanism by which A37 elicits its anticancer effects on ovarian cancer cells include impairment in mitochondrial respiration that could alter cancer cell metabolism, and a decrease in WWTR1/TAZ expression and tumorsphere formation that could suppress cancer stemness. Our findings demonstrate that inhibition of ALDH1A1 could effectively eliminate the chemoresistant ovarian cancer cells, and therefore, new strategies targeting ALDH1A1 could lead to the development of novel therapeutics for aggressive chemoresistant ovarian cancer.

Evaluation of systemic second-line therapy in recurrent or metastatic esophageal cancer

Background: More than half of patients with locally advanced esophageal cancer are unresponsive to first-line chemotherapy. To date, there is no standard second-line regimen; new agents, such as immune-checkpoint inhibitors or anti-Neurotrophic Tropomyosin-Related Kinas agents, have only been recently recommended. This study aimed to assess the benefits of classical second-line chemotherapy in terms of survival and tolerance. Materials and Methods: This retrospective analysis assessed the benefits and tolerance of different second-line regimens of chemotherapy in progressive, locally advanced or metastatic oesophageal cancer treated at the department of Radiotherapy-Oncology at the Institute of Oncology between January 2011 and January 2017. Results: The analysis found 87 patient files with a median age 59.5 years (ranging between 41 and 84), of which 40.2% (35 patients) failed the first-line platinum and 5- fluorouracil combination. Histology favoured adenocarcinomas (63.2%). The patients were in good clinical condition, with ECOG 0–1 in 86.1% (74 patients), and less than five percent had more than three metastatic sites (3.4%, 3 patients). The regimens were mostly two-drug cytotoxic (53.9%, 47 patients): FOLFIRI in 18 patients (20.7%), FOLFOX in 18 patients (20.7%), vinorelbine–platinum combination in 11 patients (12.6%), and docetaxel in 40 patients (38.7%). The median treatment duration was 7.74 weeks (range 1 to 12). The general response rate was 47.1% (41 patients), including stable disease. The median time to progression was 7.61 weeks, with a range between 1.6 and 8.6 weeks, with no differences in this respect among the fourth type of treatment received (p = 0.170). Grade 3–4 toxicities, including neutropenia, gastrointestinal problems, and metabolic disorders, were observed in 44 patients (50.6%). The median event-free survival was 2 months (range between 1 and 6.3), and 63.2% (55 patients) subsequently received a third line of chemotherapy. Conclusion: Second-line chemotherapy is still the first-choice recommendation in all fit patients with advanced oesophageal cancer. The new agents are efficacious only in cases with PD-L1 positive or high microsatellite instability.

OA09.05 Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Physician’s Choice of First-line Platinum Chemotherapy

OA09.05 Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Physician’s Choice of First-line Platinum Chemotherapy

Clinical efficacy of anlotinib plus S-1 as a second-line therapy for recurrent or metastatic esophageal squamous cell carcinoma

To investigate the efficacy of anlotinib plus S-1 for treatment of patients with recurrent or metastatic esophageal squamous cell carcinoma with failed first-line chemotherapy. Twenty-six patients with recurrent or metastatic esophageal squamous cell carcinoma patients who experienced progression after first-line paclitaxel plus platinum chemotherapy in our hospital between July, 2018 and February, 2020 were enrolled in this study. The patients received oral anlotinib along with S-1 treatment (anlotinib at 12 mg once daily and S-1 at 50 mg twice daily for two weeks; 3 weeks per cycle). The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse effects were evaluated for all the patients. No complete remission (CR) was observed in the 26 patients. Partial remission (PR) was achieved in 6 cases, stable disease (SD) in 12 cases, and progressive disease (PD) occurred in 8 cases, with an ORR of 23.1% and a DCR of 69.2% in these patients. The median PFS was 4.5 months (95%CI: 2.7-6.4 months). Univariate analysis showed that the patients with moderate or high tumor differentiation had significantly longer PFS than those with low tumor differentiation (6.1 months vs 1.9 months, P < 0.05). Multivariate analysis suggested that pathological differentiation grade (HR=6.778, 95%CI: 1.997-23.012) was an independent factor for a prolonged PFS. The adverse effects in the patients included mainly fatigue, hypertension and hand-foot syndrome, mostly of grade 1 to 2. Patients with recurrent or metastatic esophageal squamous cell carcinoma can benefit from a second-line anlotinib plus S-1 treatment, which has relatively mild adverse effects with a good safety profile.

Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus paclitaxel therapy trial

BackgroundGastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents.MethodsWe conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment.ResultsSixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6–47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(−) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity.ConclusionsProspective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer.Trial registrationThe study was registered on ClinicalTrial.gov (NCT02628951) on June 12, 2015.

Randomized phase II trial of olaparib + pembrolizumab versus olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) mutations: SWOG S2001.

TPS447 Background: Olaparib was approved in 2019 as maintenance therapy for g BRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 versus 3.8 months) for g BRCA1/2+ mPDA pts following either stable disease/response on first-line platinum chemotherapy. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of g BRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing will be eligibleif no progression after receiving 4 to 6 months of platinum chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin). Zubrod performance status (PS) 0 or 1 pts are eligible. Pts will be stratified according to first line chemotherapy, PS 0 versus 1, and disease status after first-line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires 78 evaluable pts to be accrued over 3 years. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support:NIH/NCI grants U10CA180888 and U10CA180819. Clinical trial information: TBD.