Non-platinum Chemotherapy Research Articles

780P Propensity-score matching analysis for efficacy of platinum-based versus non-platinum chemotherapy in patients with “platinum-resistant” ovarian cancer (PROC): Real-world recent cohort study

780P Propensity-score matching analysis for efficacy of platinum-based versus non-platinum chemotherapy in patients with “platinum-resistant” ovarian cancer (PROC): Real-world recent cohort study

Sarcopenia shortens overall survival of patients with platinum-resistant recurrent ovarian cancer: inverse probability of treatment-weighting analysis

ObjectiveThe association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian...

Treatment Patterns and Clinical Outcomes Among Patients with Metastatic Non-small Cell Lung Cancer Without Actionable Genomic Alterations Previously Treated with Platinum-Based Chemotherapy and Immunotherapy.

For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations. We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting. This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan-Meier analyses. Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively). Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments.

A three-arm randomized phase II study of dostarlimab alone or with bevacizumab versus nonplatinum chemotherapy in recurrent gynecological clear cell carcinoma: DOVE (APGOT-OV7/ENGOT-ov80 study).

TPS5627 Background: Recurrent gynecological clear cell carcinoma (rGCCC) is known for low objective response rates to chemotherapy. Prior preclinical and clinical data suggests potential synergy of immune checkpoint inhibitor adding bev in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting PD-1, combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. The aim of the present study is to investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. Methods: DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in patients with rGCCC. It enrolls 198 patients with rGCCC, assigning them to one of three groups in a 1:1:1 ratio: Group A (dostarlimab monotherapy), Group B (dostarlimab + bevacizumab), Group C: investigator’s choice chemotherapy. Patients with PD on Group A or Group C were allowed to crossover to Group B. Stratification factors are prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven confirmed recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina and vulva, up to 5 prior lines of therapies, disease progression within 12 months after platinum-based chemotherapy, and measurable disease. Key exclusion criteria are prior treatment with an anti PD-1, anti PD-L1, or anti PD-L2 agent. The primary endpoint is progression-free survival by investigator. The secondary endpoints include ORR, DCB, DCR, PFS2, OS, and toxicity. Exploratory objectives include immune biomarker. The study, commencing in Jan 2024, is registered with Clinicaltrials.gov (NCT06023862). Clinical trial information: NCT06023862 .

Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US

The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC. To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample. This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis. Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line. Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively). The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.

Subsequent management and outcomes after first-line PARP inhibitors progression in ovarian cancer patients

ObjectivesThis retrospective study aims to evaluating the subsequent management and outcomes after first-line PARPi progression in Chinese ovarian cancer population.MethodsClinical and pathologic variables, treatment modalities, and outcomes were assessed. We investigated the subsequent management and outcomes after first-line PARPi progression. The objective response rate (ORR) and disease control rate (DCR) parameters were evaluated to determine the response to subsequent chemotherapy. For the survival analyses, progression-free survival 1 (PFS1), PFS2, overall survival (OS) and PFS2 − PFS1 were analysed.ResultsA total of 124 patients received PARPi maintenance treatment after first-line chemotherapy during the study period in our center. 44 of them (35.5%) experienced a recurrence. The median duration of PARPi in these patients was 11.1 months (range: 1.2–75.1 months). A total of 40 patients (40/44, 90.9%) received subsequent chemotherapy with 35 (35/44, 79.5%) and 5 (5/44, 11.4%) patients received platinum-based and non-platinum-based chemotherapy in our center. 2 patients (4.5%) received target therapy and other 2 patients (4.5%) received best supportive care. 27.3% (12/44) patients received secondary cytoreduction surgery (SCS). After subsequent chemotherapy, 14 patients received PARPi retreatment as maintenance therapy. In patients who received platinum-based regimens (n = 35), 23 of 35 patients (65.7%) had complete/partial response (CR/PR), 8 of 35 (22.9%) had stable disease (SD), and 4 of 35 (12.1%) had progressive disease (PD). The ORR and DCR of patients who received subsequent chemotherapy was 65.7% and 88.6%, respectively. 15 patients (57.7%, 15/26) were reported to be platinum resistant with a platinum-free interval (PFI) of < 6 months in patients whose platinum sensitivity of the second line platinum-based regimens was evaluable. Patients who received SCS after PARPi resistant associated with a borderline better PFS2 (median PFS2: 41.9 vs. 29.2 months, P = 0.051) and a non-significantly increased PFS2-PFS1 (median PFS2-PFS1: 12.2 vs. 9.8 months, P = 0.551). Patients with a PFI ≥ 12 months had a significantly better PFS2 (median PFS2: 37.0 vs. 25.3 months, P < 0.001) and a tendency towards a better PFS2-PFS1 than those with a PFI < 12 months (median PFS2-PFS1: 11.2 vs. 8.5 months, P = 0.334). A better PFS2 was observed in patients who received second PARPi maintenance therapy (median PFS2 of 35.4 vs. 28.8 months); however, the difference was not statistically significant (P = 0.200). A better PFS2-PFS1 was observed in patients who received second PARPi maintenance therapy (median PFS2-PFS1: 13.6 vs. 8.9 months, P = 0.002) than those without.ConclusionsIn summary, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort. A trend towards higher benefit from subsequent chemotherapy after first-line PARP inhibitors progression was observed in the PFI ≥ 12 months subgroup than those with PFI < 12 months. PARPi retreatment as maintenance therapy and SCS can be offered to some patients with PARPi resistance.

Real-World Treatment Patterns and Clinical Outcomes After Platinum-Doublet Chemotherapy and Immunotherapy in Metastatic Non-Small Cell Lung Cancer: A Multiregional Chart Review in the United States, Europe, and Japan.

To characterize treatment patterns and real-world clinical outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) who developed progression on an anti-PD-1/anti-PD-L1, herein referred to as anti-PD-(L)1, and platinum-doublet chemotherapy. Eligible oncologists/pulmonologists in the United States, Europe (France, Germany, and United Kingdom), and Japan completed electronic case report forms for patients with mNSCLC (no evidence of EGFR/ALK/ROS1 alterations). Eligible patients had disease progression on/after an anti-PD-(L)1 and platinum-doublet chemotherapy (received concurrently or sequentially), initiated a subsequent line of therapy (LOT) between 2017 and 2021, and had an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 at this subsequent LOT initiation (index date). Overall survival (OS), time to treatment discontinuation (TTD), and real-world progression-free survival (rwPFS) after index were assessed using Kaplan-Meier analysis. Overall, 160 physicians (academic, 54.4%; community, 45.6%) provided deidentified data from 487 patient charts (United States, 141; Europe, 218; Japan, 128; at mNSCLC diagnosis: median age 66 years, 64.7% male, 81.3% nonsquamous, 86.2% de novo mNSCLC; at line of interest initiation: 86.0% ECOG 0-1, 39.6% liver metastases, 18.9% brain metastases, 79.1% smoking history). The most common treatment regimens upon progression after anti-PD-(L)1/platinum-doublet chemotherapy were nonplatinum chemotherapy (50.5%), nonplatinum chemotherapy plus vascular endothelial growth factor receptor inhibitor (12.9%), and platinum-doublet chemotherapy (6.6%). Median OS was 8.8 months (squamous, 7.8 months; nonsquamous, 9.5 months). Median TTD was 4.3 months (squamous, 4.1 months; nonsquamous, 4.3 months). Median rwPFS was 5.1 months (squamous, 4.6 months; nonsquamous, 5.4 months). In this multiregional, real-world analysis of pooled patient chart data, patients with mNSCLC who had disease progression after anti-PD-(L)1/platinum-doublet chemotherapy had poor clinical outcomes with various treatment regimens, demonstrating an unmet clinical need for effective options after failure on anti-PD-(L)1 and platinum-doublet chemotherapy treatments.

OPERA: a phase II trial of oregovomab plus non-platinum chemotherapy in PARP inhibitor/platinum-resistant ovarian cancer.

A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is lacking. These patients typically receive non-platinum-based chemotherapy; however, survival outcomes remain poor. Compared with chemotherapy alone, combination therapy with novel target agents can provide additional benefits to these patients. Oregovomab, an investigational murine monoclonal antibody against CA-125, has shown promising efficacy in a phase II study in patients with recurrent ovarian cancer. Herein, we described the rationale and design of OPERA/KGOG 3065/APGOT-OV6, a multicenter, investigator-initiated, two-cohort, single-arm phase II trial, aimed at examining the efficacy of oregovomab plus non-platinum-based chemotherapy in patients with PARPi/platinum-resistant ovarian cancer. The primary end point was the objective response rate, according to RECIST 1.1.Clinical Trial Registration: NCT05407584 (ClinicalTrials.gov).

Overcoming the challenges of drug development in platinum-resistant ovarian cancer.

The definition of "platinum-resistant ovarian cancer" has evolved; it now also reflects cancers for which platinum treatment is no longer an option. Standard of care for platinum-resistant ovarian cancer is single-agent, non-platinum chemotherapy with or without bevacizumab, which produces modest response rates, with the greatest benefits achieved using weekly paclitaxel. Several recent phase 3 trials of pretreated patients with prior bevacizumab exposure failed to meet their primary efficacy endpoints, highlighting the challenge in improving clinical outcomes among these patients. Combination treatment with antiangiogenics has improved outcomes, whereas combination strategies with immune checkpoint inhibitors have yielded modest results. Despite extensive translational research, there has been a lack of reliable and established biomarkers that predict treatment response in platinum-resistant ovarian cancer. Additionally, in the platinum-resistant setting, implications for the time between the penultimate dose of platinum therapy and platinum retreatment remain an area of debate. Addressing the unmet need for an effective treatment in the platinum-resistant setting requires thoughtful clinical trial design based on a growing understanding of the disease. Recent cancer drug approvals highlight the value of incorporating molecular phenotypes to better define patients who are more likely to respond to novel therapies. Clinical trials designed per the Gynecologic Cancer InterGroup recommendations-which advocate against relying solely upon the platinum-free interval-will help advance our understanding of recurrent ovarian cancer response where platinum rechallenge in the platinum-resistant setting may be considered. The inclusion of biomarkers in clinical trials will improve patient stratification and potentially demonstrate correlations with biomarker expression and duration of response. With the efficacy of antibody-drug conjugates shown for the treatment of some solid and hematologic cancers, current trials are evaluating the use of various novel conjugates in the setting of platinum-resistant ovarian cancer. Emerging novel treatments coupled with combination trials and biomarker explorations offer encouraging results for potential strategies to improve response rates and prolong progression-free survival in this population with high unmet need. This review outlines existing data from contemporary clinical trials of patients with platinum-resistant ovarian cancer and suggests historical synthetic benchmarks for non-randomized trials.

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations

IntroductionThis study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States. MethodsThe Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011–February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival. ResultsOf 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively. ConclusionsThe outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

ARTISTRY-7: phase III trial of nemvaleukin alfa plus pembrolizumab vs chemotherapy for platinum-resistant ovarian cancer.

Standard single-agent nonplatinum chemotherapy provides only modest benefit in a small proportion of patients with platinum-resistant/-refractory ovarian cancer, with objective response rates of 6-20% and progression-free survival of ≈3-4months. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel cytokine designed to capture and expand the therapeutic potential of high-dose interleukin-2 (IL-2) while mitigating its associated toxicity issues. Nemvaleukin preferentially activates cytotoxic CD8+ T cells and natural killer cells with minimal, non-dose-dependent effects on CD4+ regulatory T cells. The global, randomized, open-label, phase III ARTISTRY-7 trial will compare efficacy and safety of nemvaleukin plus pembrolizumab with chemotherapy in patients with platinum-resistant ovarian cancer. The primary end point is investigator-assessed progression-free survival. Clinical Trial Registration: GOG-3063; ENGOT-OV68; NCT05092360 (ClinicalTrials.gov).

Oregovomab and non-platinum chemotherapy in PARP inhibitor-resistant ovarian, fallopian tube, or primary peritoneal cancer patients not candidates for platinum retreatment: A multicenter, two-cohort, single-arm phase 2 trial (OPERA/KGOG 3065/APGOT-OV6).

TPS5621 Background: As PAPR inhibitors (PARPis) are becoming the standard of care option for epithelial ovarian cancer (EOC), PARPi-resistant patients are increasing. Moreover, non-platinum single agent chemotherapy in these patients has been found to elicit poor survival outcomes. Oregovomab, an investigational murine monoclonal antibody directed against CA-125, has shown promising efficacy in the previous phase II study of combinational front-line adjuvant chemotherapy. The aim of the present study is to investigate the efficacy of oregovomab + non-platinum-based chemotherapy in PARPi-resistant EOC patients not suitable for platinum-based therapy. Methods: OEPRA is a multi-centre, investigator-initiated, two-cohort, single-arm phase II trial recruiting PARPi-resistant EOC patients from five sites in South Korea. The trial includes patients with recurrent EOC who have experienced disease progression despite treatment with PARPis and who have either received bevacizumab or are not eligible for bevacizumab treatment. Mucinous histology type is excluded. Patients who have received one to three prior lines of chemotherapy are to be assigned to Cohort 1 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + pegylated liposomal doxorubicin [PLD] 40 mg/m2 q4w, n = 28), while patients who have received more than three prior lines of chemotherapy are to be assigned to Cohort 2 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + weekly paclitaxel 80 mg/m2 [D1,8,15 q4w], n = 28). A total of 56 patients will be recruited and treated with oregovomab + PLD / weekly paclitaxel until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint is objective response rate by RECIST 1.1. Accrual is expected to be completed in 2023, followed by presentation of results in 2024. The study is registered with Clinicaltrials.gov (NCT05407584). Clinical trial information: NCT05407584 .

Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study

(Abstracted from J Clin Oncol 2023;41(13):2436–2445 Approximately 80% of patients with ovarian cancer experience recurrence after platinum-based chemotherapy, and unfortunately nearly all will eventually develop platinum-resistant ovarian cancer (PROC). Treatment in this setting consists of nonplatinum chemotherapy with or without bevacizumab; however, each successive line of therapy in PROC is associated with progressively lower response rates.

Chemotherapy response in low-grade serous ovarian carcinoma at a comprehensive cancer center: Readdressing the roles of platinum and cytotoxic therapies.

Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease. Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed. Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p=.027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively. Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.

Could S-1-based non-platinum doublet chemotherapy be a new option as a second-line treatment for advanced non-small cell lung cancer patients? A multicenter retrospective study.

For patients who have contraindications to or have failed checkpoint inhibitors, chemotherapy remains the standard second-line option to treat non-oncogene-addicted advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of S-1-based non-platinum combination in advanced NSCLC patients who had failed platinum doublet chemotherapy. During January 2015 and May 2020, advanced NSCLC patients who received S-1 plus docetaxel or gemcitabine after the failure of platinum-based chemotherapy were consecutively retrieved from eight cancer centers. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. By using the method of matching-adjusted indirect comparison, the individual PFS and OS of included patients were adjusted by weight matching and then compared with those of the docetaxel arm in a balanced trial population (East Asia S-1 Trial in Lung Cancer). A total of 87 patients met the inclusion criteria. The ORR was 22.89% (vs. 10% of historical control, p < 0.001) and the DCR was 80.72%. The median PFS and OS were 5.23 months (95% CI: 3.91-6.55 months) and 14.40 months (95% CI: 13.21-15.59 months), respectively. After matching with a balanced population in the docetaxel arm from the East Asia S-1 Trial in Lung Cancer, the weighted median PFS and OS were 7.90 months (vs. 2.89 months) and 19.37 months (vs. 12.52 months), respectively. Time to start of first subsequent therapy (TSFT) from first-line chemotherapy (TSFT > 9 months vs. TSFT ≤ 9 months) was an independent predictive factor of second-line PFS (8.7 months vs. 5.0 months, HR = 0.461, p = 0.049). The median OS in patients who achieved response was 23.5 months (95% CI: 11.8-31.6 months), which was significantly longer than those with stable disease (14.9 months, 95% CI: 12.9-19.4 months, p < 0.001) or progression (4.9 months, 95% CI: 3.2-9.5 months, p < 0.001). The most common adverse events were anemia (60.92%), nausea (55.17%), and leukocytopenia (33.33%). S-1-based non-platinum combination had promising efficacy and safety in advanced NSCLC patients who had failed platinum doublet chemotherapy, suggesting that it could be a favorable second-line treatment option.

Abstract P4-01-20: Phase IV study evaluating talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a somatic or germline BRCA1/2 mutation (ViTAL) – Analysis of cohort 1 according to hormonal receptor status

Abstract Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that has demonstrated clinical benefit in EMBRACA Phase III trial for patients with germline BRCA1/2 mutated locally advanced or metastatic HER2- breast cancer. Objective: The aim of the study is to ensure the effectiveness and safety of TALA in real-life setting among patients with locally advanced or metastatic HER2- breast cancer, with somatic or germline BRCA1/2 mutation. Methods: ViTAL is an ambispective, multicentric, longitudinal, phase IV study. It includes two ambispective cohorts: - Cohort 1: patients treated through the French Early Access Program and inclusion of patients with somatic BRCA1/2 mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted in 09/21/2021. Here we present the results of the primary and some secondary endpoints for cohort 1. Results: From November 2018 to May 2021, 86 patients were included in Cohort 1, with updated results after a median follow-up of 17.3 months (11.2 - 24.4). Patients’ characteristics are 53.5% of ER+ BC/46.5% of TNBC (refer to the table). The median Time to Treatment Discontinuation (mTTD) was 9.0 months [range 6.0; 11.5] with 37.7% of patients still on treatment at 12 months. Subgroup analysis shows similar mTTD according HR status, germline vs somatic mutation and prior platinum exposure (refer to the table). The Clinical Benefit Rate assessed by the investigators is 82.4% (Complete Response for 25.7%, Partial response R for 32.4% and stable disease for 24.3%). The median of duration of CNS metastases control was 6.6 months, and 80.0% of patients had control of CNS metastases during TALA. Out of the 85 treated patients, 69 patients (80,2%) experienced a TALA permanent discontinuation for progressive disease (84.1%), toxicity (10.1%), cancer-related death (1.4%), or other reasons (1.4%). After discontinuation of TALA, 65.1% of patients received a subsequent treatment with a TTD of 2.3 months [1.7; 2.7]. The most common subsequent treatments were non-platinum chemotherapy (64.3%), platinum chemotherapy (19.6%) and others (19.1%). At least one adverse events (AEs) was recorded in 74.4% of patients. Hematologic AEs (any grade) occurred in 48.8% (anemia 27.9%, thrombocytopenia 12.8%, neutropenia 10.5%). Most common non-hematologic AEs were alopecia (8.1%) and asthenia (7.0%). Related Serious Hematologic AEs occurred in 10 patients (11.6%) including 7 (8.1%) Anemia. Related Serious Non-hematologic AEs (vomiting, pyelonephritis and ascitis) were seen in 3 patients (3.6%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 36 (41.9%), 24 (27.9%), and 7 (10.1%) patients respectively. The mOS is expected to be reached at the time of the congress, with 51.9% of patients still alive at 24 months. Conclusions: ViTAL is the largest study that reports real-word data with TALA. Outcomes and safety in Cohort 1 are consistent with the results of EMBRACA study and give additional data on subgroups of interest (ie patients previously treated with carboplatin, presence of CNS). (Litton et al. NEJM 2018) mTTD on subgroups of interest Patients’ characteristics Citation Format: Delphine Loirat, Marie Duboys de la barre, Jean-Christophe Thery, Ioana Hrab, Christelle Jouannaud, Jean-Loup Mouysset, Laura Salabert, Pauline Soibinet, Audrey Mailliez, Romain Valery, Anne Creisson, Cristian Villanueva, Nadine Dohollou, Jean-david Fumet, Thomas grellety, Nathalie Perez-staub, Emma Lachaier, Aurore Iltis-roux, Miguel delbado, Abeer Najem, Romuald Le Scodan, Elsa Curtit, kais aldabbagh, Pascal Pujol, thibault DE LA MOTTE ROUGE. Phase IV study evaluating talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a somatic or germline BRCA1/2 mutation (ViTAL) – Analysis of cohort 1 according to hormonal receptor status [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 P4-01-20.

Abstract P4-01-04: Phase IV multicenter study evaluating RWE and the safety of talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a BRCA1/2 mutation (ViTAL) - Cohort 2: patients treated according to the EMA

Abstract Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that has demonstrated clinical benefit in EMBRACA Phase III trial for patients with germline BRCA1/2 (BRCA1/2)-mutated locally advanced or metastatic HER2- breast cancer. Objective: The aim of the study is to ensure the effectiveness and safety of TALA in the real-world setting among patients with locally advanced or metastatic HER2- breast cancer, with somatic or germline BRCA1/2 mutation. Methods: ViTAL is an ambispective, multicentric, longitudinal, phase IV study. It includes two ambispective cohorts: - Cohort 1: patients treated through the French Early Access Program and inclusion of patients with somatic BRCA1/2 mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted in 09/21/2021. The primary endpoint of the study is the Time to Treatment Discontinuation (TTD) which is defined as time between the date of first dose of TALA and the date of last dose or death. Results: From November 2018 to May 2021, 85 patients were included in Cohort 2, Patients’ characteristics are: - a median age of 49.0 years; - 65.8% ER+ BC/34.2% TNBC; - 42.1% mBRCA1/55.3 % mBRCA2/2,6% mBRCA1 and mBRCA2. - 85.7% ECOG PS 0 or 1; - 23.4% de novo mBC. - Visceral, bones and CNS metastases were found in 59.0%, 61.5% and 10.3% of patients respectively. - No breast or ovarian cancer family history at 1st degree was found in 39 patients (50.0%). - 38.5% were chemo-naïve; - 21.8% received prior platinum in (neo)adjuvant or metastatic setting, with a median of prior cytotoxic regimen of 1 - For patients with ER+/HER2- ABC the median number of prior endocrine therapy was 1 and 62.0% of these patients received a CDK4/6 inhibitor prior to TALA. - 8 patients (10.3%) had CNS metastases. Out of the 78 treated patients, 57 patients (73.0%) experienced a TALA permanent discontinuation for Progressive disease (80.7%), toxicity (12.3%), cancer-related death (1.8%), or other reasons (1.8%). The median TTD for TALA is 9.6 months [6.7;10.8] with 34.5% of patients still on treatment at 12 months. After discontinuation of TALA, 59.0% of patients received a subsequent treatment with a TTD of 3.9 months [2.1; 45]. The most common subsequent treatments were non-platinum chemotherapy (67.4%), platinum therapy (6.5%) and other (26.1%). The Clinical Benefit Rate assessed by the investigators is 87.6% (Complete Response for 14.1%, Partial Response for 56.3% and Stable Disease for 17.2%). The median duration of CNS metastases control was 10.2 months, and 25.0% of patients had a control of CNS metastases. At least one adverse events (AEs) was recorded in 67.9% of patients. Hematologic adverse events (AEs) (any grade) occurred in 55.1% (anemia 37.2%, thrombocytopenia 16.7%, neutropenia 15.4%). Most common non-hematologic AEs were Nausea (15.4%) and asthenia (15.4%). Related Serious Hematologic AEs occurred in 6 patients (7.7%) including 3 (3.8%) thrombocytopenia and 3 (3.8%) anemia. Related Serious Non-hematologic AEs (metrorrhagia) were seen in 1 patient (1.3%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 26 (33.3%), 22 (28.2%), and 7 (12.3%) patients respectively. The mOS is not mature for this analysis. Conclusions: ViTAL is the largest study that reports real-word data with TALA. Outcomes and safety in Cohort 2 (patients treated with TALA according to the European Marketing Approval), are consistent with the results of EMBRACA study and with the Cohort 1. (Litton et al. NEJM 2018) Citation Format: Delphine Loirat, Marie Duboys de la barre, Cristian Villanueva, Audrey Mailliez, Nicolas Isambert, Lionel Moreau, Emmanuelle Jacquet, Dominique Spaëth, Anne Creisson, Christelle Jouannaud, Eric Legouffe, Miguel delbado, Laura Deiana, Pauline Soibinet, Ioana Hrab, Thomas grellety, Nadine Dohollou, Raffaele Longo, Jean-Christophe Thery, Jean-david Fumet, Sellam Zineb, Pascal Pujol, thibault DE LA MOTTE ROUGE. Phase IV multicenter study evaluating RWE and the safety of talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a BRCA1/2 mutation (ViTAL) - Cohort 2: patients treated according to the EMA [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 P4-01-04.

Abstract OT3-11-02: SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL

Abstract Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [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 OT3-11-02.

Characteristics and outcomes for patients (pts) with metastatic small cell urothelial carcinoma (mSCUC).

522 Background: mSCUC is an aggressive cancer with historically poor outcomes. Methods: We performed a retrospective analysis of 216 pts with mSCUC treated at MD Anderson from 1985-2020. We captured baseline demographic and clinical characteristics, metastatic sites, systemic treatments, and survival. Median overall survival (mOS) was calculated from start of frontline (1L) therapy for metastatic disease. Results: Median age was 67 years, 84% male sex, 91% primary tumor in bladder, and 88% white race. Histology included pure SCUC (30%), predominant SCUC (44%), focal SCUC (25%) and large cell (1%). Metastatic sites were lymph nodes (54%), bone/peritoneum (39%), liver (38%), brain (31%) and lung (26%). Brain metastases frequency varied across histology (pure SCUC 48%, predominant SCUC 24.5%, focal SCUC 24%, p=0.06). Treatment regimens and mOS by frontline regimen are listed (Table). mOS was 11.91 months for treated pts with sufficient follow up (n=155). mOS by 1L treatment: EP (9.51 months), IA/EP (14.10 months), other platinum chemotherapy (13.26 months), nonplatinum chemotherapy (9.74 months), immune checkpoint inhibitor (ICI) (6.51 months), EP+ICI (undefined). Of 140 pts treated with 1L chemotherapy, 43 (31%) were able to receive second line (2L) therapy. mOS among those who received 2L chemotherapy (n=27) was 13.65 months vs those who received 2L ICI (n=16) was 22.53 months (HR=0.53, 95% CI=0.26-1.10; p=0.11). Conclusions: mSCUC is a devastating malignancy with high degree of brain involvement, and poor prognosis. 1L ICI therapy alone has suboptimal survival outcomes and a chemotherapy backbone remains necessary. A deeper understanding of SCUC’s driver biology is essential for developing better therapies. [Table: see text]

147P Activity of single-agent PD-1/PD-L1 inhibitors in 1st-line (1L) “platinum-ineligible” patients (pts) with metastatic urothelial cancer (mUC) in real-life clinical practice

Data from real-practice in more than 4,000 pts diagnosed of mUC in the US show that only 33.2% are receiving systemic 1L platinum-based ( approaches (Morgans et al. ESMO 2021). Surprisingly, in the same series up to 45.9% of these pts were treated with PD-1/PD-L1 inhibitors or non-platinum chemotherapy. Recently, a consensus-based definition was proposed to define “platinum-ineligible” mUC population i(Gupta et al. ASCO 2022). Since this “platinum-ineligible” population is becoming more and more relevant in daily practice, we collected our experience with single agent PD-1/PD-L1 inhibitors in 1L mUC and compared the efficacy between “cis-ineligible” vs “platinum-ineligible” populations.