First-line Platinum-based Therapy Research Articles

Race- associated molecular differences in uterine serous carcinoma

PurposeEndometrial cancer (EMCA) is the most common gynecologic malignancy, and new diagnoses are increasing in the United States. Black patients are more likely to present with advanced stage, be diagnosed with high-risk uterine serous carcinoma (USC) and die of their cancer.MethodsPatients with endometrial adenocarcinoma who received tumor FoundationOne CDx testing at our institution between January 2017 and August 2022 were identified. Genomic alterations, demographic and clinical characteristics were collected. Descriptive statistics and Fisher’s exact test were used to analyze data.ResultsA total of 289 patients (29.4% Black and 52.6% White) with advanced or recurrent endometrial adenocarcinoma underwent FoundationOne CDx testing. USC comprised 26.3% (76 of 289) of tested tumors. Of USC tumors, 33 of 76 (44%) were of Black race. USC occurred more frequently in Black patients (33 of 85 [38.8%] Black patients compared to 30 of 152 [19.7%] White patients, p<0.05). Among USC, CCNE1 amplification occurred more frequently in Black patients than in White patients (12 of 33 [36.36%] vs 2 of 30 [6.67%], p<0.05) while PI3K/AKT/mTOR pathway mutations occurred less frequently (16 of 33 [48.5%] vs 26 of 33 [86.7%], p=0.17). Among patients with CCNE1 amplification 73.3% (11 of 15) progressed on or within 12 months of first-line platinum-based therapy. CCNE1 amplification had significantly shorter median overall survival (97.3 months vs 44.3; HR (95%CI): 7.1 (10.03, 59.4) p< 0.05).ConclusionsBlack patients constituted 44% of patients with USC in our study and had an increased frequency of CCNE1 amplification. Patients whose tumors harbored CCNE1 amplification had shorter overall survival. Identifying actionable mutations in this high unmet need population is crucial to improving outcomes among Black patients with uterine malignancy. Development of new targeted-therapies will need to keep these alterations at the forefront as trials are being designed.

Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial

There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations. In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m2 on day 1 and either plinabulin (30 mg/m2) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed. Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group. Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population. BeyondSpring Pharmaceuticals.

Eftilagimod Alpha (Soluble LAG3 Protein) Combined with Pembrolizumab as Second-Line Therapy for Patients with Metastatic Head and Neck Squamous Cell Carcinoma.

Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability. In this multinational phase II trial using Simon's two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies. Between March 2019 and January 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy, and 40.5% were pretreated with cetuximab; 53.1% of patients had PD-L1 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed. Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma(HNSCC), thus supporting further evaluation of this combination in earlier treatment lines.

Paclitaxel oral solution versus paclitaxel injection as second-line therapy in advanced gastric cancer: A randomized, open-label, non-inferiority phase 3 trial.

4051 Background: Paclitaxel injection (paclitaxel IV) is category 1 preferred regimen in the second-line therapy of gastric cancer. Safer and more convenient paclitaxel oral solution (Liporaxel), the world’s first oral formulation, has been initially approved in Korea for treatment of gastric cancer. This study aimed to determine non-inferiority in efficacy and safety profile of paclitaxel oral solution versus paclitaxel IV, as monotherapy in larger population with unresectable locally advanced, recurrent or metastatic gastric cancer in China. Methods: This is a randomized, open-label, non-inferiority phase 3 trial conducted at 53 centers in China. Patients with unresectable or recurrent or metastatic gastric cancer progressed after fluoropyrimidine- or fluoropyrimidine plus platinum-based first-line therapy were randomly assigned 1:1 (stratified by gastrectomy, ECOG PS and prior chemotherapy) to receive oral paclitaxel (200mg/m2 twice daily on days 1, 8, 15 every 4 weeks) or paclitaxel IV (175mg/m2 on day 1 every 3 weeks). The co-primary endpoints were blind independent review committee (BIRC)-assessed progression-free survival (PFS) and overall survival (OS), with non-inferiority margin of hazard ratio (HR) of 1.18 and 1.16 in statistical comparison, respectively. Results: From April 22, 2019, to January 31, 2022 (data cut-off), 536 patients were randomized to oral paclitaxel (n=268) or paclitaxel IV (n=268), with median follow-up of 13.4 vs. 12.6 months, respectively. The PFS showed non-inferiority of oral paclitaxel to paclitaxel IV with median BIRC-assessed PFS 3.02 months (95% confidence interval [CI]: 2.69, 3.71) in oral paclitaxel vs. 2.89 months (95% CI: 2.53, 3.48) in paclitaxel IV (HR 0.894, 95% CI: 0.719, 1.112, p=0.311). The OS (cutoff on February 15, 2023) showed superiority of oral paclitaxel over paclitaxel IV with median OS 9.13 months (95% CI: 7.72, 10.97) in oral paclitaxel vs. 6.54 months (95% CI: 5.75, 7.26) in paclitaxel IV (HR 0.770, 95.5% CI: 0.635, 0.934, p=0.006). For the treatment-related adverse events (TRAEs), oral paclitaxel decreased neuropathy incidence (22.3% vs. 38.7% all grade) and no hypersensitivity occurred in oral paclitaxel without premedication. The most common ≥Grade 3 TRAEs were neutrophil count decreased (47.9% in oral paclitaxel vs. 54.5% in paclitaxel IV), white blood cell count decreased (41.5% vs. 35.3%) and anemia (16.6% vs. 10.9%). Grade 5 TRAEs were at low with comparable incidences (four [1.5%] vs. three [1.1%]). Conclusions: The study showed statistical non-inferiority of paclitaxel oral solution in PFS and statistically significant and clinically meaningful improvement in OS as compared to paclitaxel IV, with clinically manageable safety profile, supporting paclitaxel oral solution as second-line treatment option for patients with gastric cancer. Clinical trial information: CTR20190050.

Efficacy and safety of combination therapy with envafolimab and lenvatinib in patients with endometrial cancer after failure of first-line platinum-based therapy.

Efficacy and safety of combination therapy with envafolimab and lenvatinib in patients with endometrial cancer after failure of first-line platinum-based therapy.

Treatment patterns in metastatic bladder cancer in Japan: results of the CancerMPact® survey 2020.

Aim: To assess physician-reported treatment of metastatic bladder cancer in Japan. Methods: 76 physicians completed the CancerMPact® survey in July 2020, considering patients treated within 6months. Results: Physicians treated a mean of 38.1 patients per month. Of cisplatin-eligible and -ineligible patients, 97.6and 89.3%, respectively, received first-line platinum-based therapy, most commonly cisplatin plus gemcitabine (72.9%) and carboplatin plus gemcitabine (59.7%). 1.6and 5.6% received first-line immune checkpoint inhibitors, respectively. 48.4and 45.0%, respectively, progressed and received second-line therapy, most commonly with pembrolizumab (61.7%). Conclusion: In 2020, most patients with metastatic bladder cancer in Japan received first-line platinum-based chemotherapy; however, >50% received no subsequent treatment, highlighting the need for new treatment regimens to improve outcomes and maximize first-line treatment benefits.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

Progression-free survival in patients receiving first-line platinum-based therapy in Argentina: OCEANIA study.

e17593 Background: OCEANIA is a retrospective database study that evaluated treatment patterns and outcomes in a cohort of patients diagnosed with all ovarian cancer (OC) types in private healthcare settings in Brazil and Argentina. The present analysis described up to 5-year real-world (RW) outcomes in an OC cohort of patients who received first-line platinum-based treatment (PBT) in Argentina. Methods: Patients with an OC code diagnosed from 2010 to 2019 who received a PBT alone or in combination with other therapeutic modalities (other antineoplastics, surgery, and/or radiotherapy) were selected from a private healthcare provider’s database (Hospital Italiano de Buenos Aires) in Argentina. Frequency of PBT patients by FIGO (International Federation of Gynecology and Obstetrics) stage was described. Cumulative risk of progression to subsequent treatment or death was calculated for one year up to five years after the end of first PBT from the survival analysis (using Kaplan–Meier analyses). RW progression-free survival (RW-PFS) was defined as the time between the end of first PBT and the beginning of subsequent treatment or death; patients who were lost to follow-up were censored at the end of the study period. Results: From 741 OC patients in the database, 321 (43.3%) were exposed to a PBT. Among this population, 89.4% had information about FIGO staging: 39 (13.6%) were stage 1; 23 (8.0%) stage 2; 195 (67.9%) stage 3; and 30 (10.5%) stage 4. During the follow-up period, 209 events were recorded, including 181 progressions to subsequent treatments and 28 deaths. The unadjusted mean (standard deviation) and median RW-PFS were 16 (22.3) months and 6 months, respectively. The adjusted cumulative risks of progression or death for years 1–5 were 53.8%, 67.6%, 71.2%, 74.4%, and 76.1%, respectively. Conclusions: Almost two thirds (65.1%) of patients with OC exposed to PBT progressed to subsequent treatment or death during follow-up. The greatest risk of progression was observed within the first year after end of PBT, likely because almost 80% of patients were at stages 3 and 4 and the therapeutic options available during the study period were limited. Funding: GSK213815.

CO161 Evaluation of Surrogate Endpoints for Overall Survival in Platinum-Resistant/Refractory Ovarian Cancer

Recent publications did not find strong evidence to support the surrogacy of progression-free survival (PFS) for overall survival (OS) in patients with ovarian cancer patients undergoing first-line platinum-based therapy. The surrogacy analysis could be confounded by multiple factors, including post-relapse treatments. To investigate this topic further we assessed whether PFS may be a surrogate for OS in patients with platinum-resistant/refractory ovarian cancer (PROC).

The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non-Small Cell Lung Cancer.

We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients). The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

Efficacy and outcomes of ramucirumab and docetaxel in patients with metastatic non-small cell lung cancer after disease progression on immune checkpoint inhibitor therapy: Results of a monocentric, retrospective analysis.

Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset.

Selection Criteria and Treatment Outcome for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Unfit for Platinum-Based First-Line Therapy: Results of the MOON-OSS Observational Trial.

Limited evidence is available concerning the selection criteria and the outcomes of platinum unfit newly diagnosed advanced NSCLC patients receiving single-agent chemotherapy. We retrospectively collected data on consecutive, stage IIIB-IV, EGFR/ALK negative and PD-L1 &lt; 50% NSCLC patients treated with first-line single agent chemotherapy. Baseline characteristics, outcome measures and toxicities were recorded, as well as criteria according to which treatment selection was made and what percentage of patients did not receive a first-line platinum-based chemotherapy. Two-hundred and twenty-one patients were included. Median age was 79 (range 56-92) years, M/F 165(74.6%)/56(25.4%), ECOG performance status (PS) 0/1/ ≥ 2 23(10.9%)/94(42.5%)/103(46.6%), with a median of two serious comorbidities. A median of 25% (range 10%-30%) of newly diagnosed NSCLC did not receive a first-line platinum combination. Clinical criteria according to which decision was made were older age (76.5%), comorbidities (72%), poor PS (55.2%) and familiar or social issues (10%). Single-agent treatment consisted of oral metronomic vinorelbine (MetV 78.6%), gemcitabine (Gem 10%), oral standard vinorelbine (Vin 8.2%) and other (O 3.2%). Median progression-free survival (PFS) and overall survival (OS) of single agent treatments ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. All grade toxicities did not differ among single agents, while grade 3-4 toxicities were less frequent with MetV. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 &lt; 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (&gt;70 years), comorbidities and poor PS. An oral treatment was frequently proposed with MetV being the most frequent choice according to its safety profile.

Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma.

Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa, a novel engineered cytokine, in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (326)

Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected. Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected.

Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes.

To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Cost-effectiveness of Olaparib plus Bevacizumab versus Bevacizumab in the maintenance of patients with HRD+ advanced ovarian cancer after response to first-line platinum-based chemotherapy in Spain.

e17591 Background: Olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), monotherapy as first-line maintenance treatment has shown to be cost-effective in ovarian cancer (OC) patients with BRCA mutations in Spain. Regardless of BRCA status, patients with homologous recombination deficiency positive (HRD+) also benefit from PARPi following first-line platinum-based therapy. PAOLA-1 trial confirmed that adding Olaparib to bevacizumab (BEV) significantly increased progression-free survival (PFS) in OC patients. The aim of this study was to assess the cost-effectiveness of Olaparib plus BEV versus BEV monotherapy for the maintenance treatment of HRD+ advanced OC patients after response to first-line platinum-based therapy plus BEV from Spanish National Health System perspective. Methods: A lifetime partitioned survival model with monthly cycles and four health states (PFS, first progression, second progression, and death) was developed. Long-term survival defined as 60 months was included in the mixed survival model as a landmark to extrapolate PFS from the PAOLA-1 trial. Weibull distribution was selected as the most accurate survival model for PFS extrapolation. Time to second progression, and overall survival (OS) were extrapolated using parametric survival models. Mortality was obtained from the OS and adjusted by Spanish mortality rates. Health state utilities and adverse event (AE) frequencies were obtained from PAOLA-1. An expert panel validated data and assumptions. Direct costs including drug acquisition and administration, follow-up, subsequent therapies, AE, and end-of-life were obtained from local sources. A 3% annual discount rate was applied to costs and outcomes. The incremental cost-effectiveness ratio (ICER) was calculated as cost per quality-adjusted life-years (QALYs) gained. One-way and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the model. Results: Base-case analysis of Olaparib plus BEV compared with BEV showed an ICER of €24,371 per QALY gained. Discount rates applied to outcomes and the cost of Olaparib generated the most significant changes in the ICER. PSA demonstrated that Olaparib plus BEV had a 49.5% and 90.3% probability of being cost-effective versus BEV at a willingness-to-pay of €25,000 and €60,000 per QALY gained, respectively. Conclusions: Olaparib plus BEV is a cost-effective maintenance therapy compared with BEV for patients with HRD+ advanced OC in Spain.[Table: see text]

Tolerability, safety, and preliminary antitumor activity of fuzuloparib in combination with SHR-1316 in patients with relapsed small cell lung cancer: a multicenter, open-label, two-stage, phase Ib trial.

BackgroundSecond-line treatment options for small cell lung cancer (SCLC) are limited. Preclinical research shows that inhibition of poly (ADP-ribose) polymerase (PARP) could upregulate programmed death-ligand 1 (PD-L1), and thus render cancer cells more sensitive to immune checkpoint inhibitors. This study investigated the tolerability, safety, and preliminary antitumor activity of fuzuloparib (a PARP inhibitor) plus SHR-1316 (a PD-L1 inhibitor) for relapsed SCLC.MethodsPatients with SCLC who failed previous first-line platinum-based therapy were enrolled in this two-stage phase Ib trial. In stage 1, 2 dose levels were designed: fuzuloparib 100 mg or 150 mg twice daily plus SHR-1316 600 mg every 2 weeks, with 6 patients in each dose level. Based on the tolerability during the first 28-day cycle and the preliminary antitumor activity in stage 1, a recommended phase II dose (RP2D) was determined and introduced in the stage 2 expansion phase. The primary endpoints were safety and RP2D in stage 1 and objective response rate (ORR) in stage 2.ResultsA total of 23 patients were enrolled, with 16 receiving fuzuloparib 100 mg plus SHR-1316 and 7 receiving fuzuloparib 150 mg plus SHR-1316. At data cutoff on April 23, 2021, the median follow-up duration was 6.4 months (IQR, 3.0–9.7 months). All patients discontinued study treatment. One patient receiving fuzuloparib 150 mg plus SHR-1316 had clinically significant toxicities, and fuzuloparib 100 mg plus SHR-1316 was considered as the RP2D. In the RP2D cohort, the confirmed ORR was 6.3% (95% CI: 0.2–30.2%), and the disease control rate was 37.5% (95% CI: 15.2–64.6%). The median progression-free survival was 1.4 months (95% CI: 1.3–2.8 months), and the median overall survival was 5.6 months (95% CI: 3.0–16.7 months). Grade ≥3 treatment-related adverse events (TRAE) occurred in 8 patients (34.8%). No treatment-related death occurred, and no patients discontinued treatment due to TRAEs.ConclusionsFuzuloparib combined with SHR-1316 failed to improve the outcomes in unselected patients with relapsed SCLC. Future studies with biomarker analysis are warranted to select patients most likely to benefit from this combination treatment. Fuzuloparib 100 and 150 mg plus SHR-1316 were both tolerable with no new signals observed.

The impact of antibiotic selection and interval time among advanced non-small cell lung cancer patients receiving prior antibacterial treatment and first-line chemotherapy.

To determine whether antibiotic use before chemotherapy is associated with chemotherapy responses and patient outcomes among NSCLC patients and define the optimal interval between chemotherapy initiation and antibiotic treatment. One thousand four hundred and four advanced NSCLC patients receiving first-line platinum-based doublets therapy were retrospectively analyzed. Kaplan-Meier curve evaluated the impact of antibiotic use and type of antibiotics on the survival of patients. The factors affect the patient's prognosis were further confirmed by Cox regression. The optimal interval between antibiotic treatment and the initiation of chemotherapy was determined by the X-tile program. NSCLC patients of 33.5% advanced underwent broad-spectrum antibiotic treatment prior to chemotherapy. In the chemotherapy only (Chemo) and chemotherapy plus antiangiogenesis (Chemo-angio) treatment groups, prior antibiotic treatment was associated with worse OS (Chemo: 13.8 vs. 17.6 months, p < 0.001; Chemo-angio:11.9 vs. 18.1 months, p=0.012) and PFS (Chemo: 3.7 vs. 5.8 months, p < 0.001; Chemo-angio: 3.1 vs. 5.9 months, p < 0.001). Cox regression analysis revealed prior antibiotic administration as an independent predictor of OS and PFS (HR for PFS/OS: 1.925/1.452, both p < 0.001). Antibiotic usage duration (HR for PFS/OS: 1.030/1.036, p=0.009/0.001) and type (PFS/OS: p < 0.001/p=0.01) also showed significant association with patient prognosis, with calculated interval time cutoff values of 2, 4, and 2 days for fluoroquinolones, β-lactamase inhibitors, and cephalosporins, respectively. Antibiotic use before first-line chemotherapy was associated with poor results in advanced NSCLC patients; treatment length and type being strongly correlated with patient outcomes. Appropriate prolongation of the time between two treatments may enhance patient survival. Further prospective research is however necessary.

Treatment Outcomes in Neuroendocrine Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is rare and has a poor prognosis; its clinical course and treatment outcomes are also unclear. This study investigated the clinical characteristics, clinical course, and treatment outcomes of patients with NEPC. This retrospective study investigated 14 patients histologically diagnosed with NEPC at Kanazawa University Hospital between 2000 and 2019. Overall survival (OS) and progression-free survival (PFS) were retrospectively analyzed using the Kaplan-Meier method. Additionally, log-rank tests were used to compare survival distributions. We included 14 patients histologically diagnosed with NEPC among 1,845 patients with prostate cancer. Four patients (0.22%) were diagnosed with de novo NEPC, and ten patients were diagnosed with NEPC during treatment. First-line platinum-based therapy's objective response rate (ORR) was 66.7%, and disease control rate was 91.7%; median PFS was 7.5 months. The median OS from NEPC diagnosis was 20.3 months. The median OS of the liver metastasis (-) group was 31.6 months, and that of the (+) group was 9.4 months (p=0.03, hazard ratio=0.24). The median OS of the somatostatin receptor scintigraphy (SRS)-positive group was 31.6 months, and that of the SRS-negative group was 10.6 months (p=0.04, hazard ratio=0.14). Platinum-based chemotherapy is effective to some extent, but the duration of response is not sufficient; therefore, new treatment options are needed. This is the first study to show that SRS findings and the presence of liver metastases might be prognostic predictors of NEPC.

Survival Prediction by Baseline Systemic Immune-inflammation Index (SII) and its Changes During First-line Platinum-based Treatment in a Caucasian Population of Patients With Metastatic Urothelial Carcinoma (MUC).

Systemic immune-inflammation index (SII) predicts survival of patients with various malignancies. This study explored the prognostic value of SII in metastatic urothelial carcinoma (MUC) subjects. We evaluated 181 consecutive MUC patients treated with first-line platinum-based therapy. Karnofsky performance status <80% and visceral metastasis were present in 18.2% and 46.4% of patients, respectively. SII was based on platelet × neutrophil/lymphocyte counts. Study population was dichotomized by median into high and low SII groups before the initiation of chemotherapy and at week 6. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. At median follow-up of 9.6 months, 174 patients experienced disease progression and 173 died. Patients with low SII at baseline and at week 6 had significantly better PFS (HR=0.58; p=0.0002 and HR=0.55; p<0.0001) and OS (HR=0.54; p<0.0001 and HR=0.54; p<0.0001) compared to patients with high SII. Independent prognostic value of SII was confirmed in a multivariate analysis. High SII before chemotherapy that persists at week 6 negatively affects survival. SII at baseline can be used in the stratification of patients within clinical trials and in clinical practice.