First-line Maintenance Therapy Research Articles

Impact of postoperative residual disease in patients with primary epithelial ovarian cancer in the era of maintenance therapies with targeted agents: A systematic review and meta-analysis.

e17555 Background: To investigate the impact of residual disease after cytoreductive surgery for epithelial ovarian cancer (EOC) on survival outcomes in the era of targeted maintenance approaches, including bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitor administration. Methods: We searched relevant literature from the MEDLINE, Embase, and Cochrane Library databases to identify randomized controlled trials and prospective clinical trials of primary EOC published between 1 January 2000 and 22 September 2022. To evaluate the impact of postoperative residual tumors on PFS and OS, we constructed a linear regression model for log-transformed median progression-free survival (PFS) and overall survival (OS). Patients with and without first-line maintenance therapy were examined. The protocol was registered in the PROSPERO (CRD42021265810). Results: In total, 97 trials with 41,799 patients were included: 2476 received PARP inhibitors, and 6920 received bevacizumab. The median rate of complete cytoreduction was 36.3% (range, 0–99.4%), regardless of the timing of surgery. Multivariable analysis of the linear regression model of all studies revealed that the median OS increased by 12.97% for every 10% increase in complete cytoreduction rates, independently of the use of systemic maintenance. In subgroup analysis of patients with maintenance therapies, the effect of complete tumor clearance was potentiated, with a median OS increased by 19.13% for every 10% increase in complete cytoreduction rates. The previously described significant effect of total macroscopic tumor clearance of PFS could not be retained when adjusting for maintenance treatment. Conclusions: Total macroscopic tumor clearance at the initial presentation of EOC significantly prolongs OS. Our results establish the importance of complete surgical cytoreduction in the era of novel targeted systemic agents.

Clinical features of long-term survivors with advanced high-grade serous ovarian cancer.

e17575 Background: Most patients diagnosed with high-grade serous ovarian cancer (HGSOC) at advanced stages (FIGO III&IV) have limited survival. However, approximately 30% of patients survive more than 5 years, some of them without relapse. A better understanding of these patients may uncover novel factors contributing to their long survival beyond those known to be related to HGSOC prognosis (age, stage and residual disease after surgery). This descriptive study aims to analyze the clinical characteristics of these exceptional survivors and describe them in contrast to patients with worse survival in a cohort of patients diagnosed before the introduction of PARP inhibitors as first-line maintenance therapy. Methods: A descriptive analysis of patients newly diagnosed with advanced HGSOC at our University Hospital between 2009 and 2018 was conducted. We report clinical characteristics of long-term survivors (LTS), defined as patients alive after 5 years(y) from the date of diagnosis and characteristics of patients who survived less than two years from the date of diagnosis, classified as short- term survivors (STS). Results: Among 195 patients with advanced HGSOC 42 (21,5%) survived less than 2y and 48 (24,6%) more than 5y, 18 of them (37,5%) without relapse. The Median age was 61.1y for LTS and 64.8 for STS. In the LTS group, 77.1% of patients were stage III, and 22.9% were stage IV. In the STS group, the distribution of patients with stage III and IV was 42.9% and 57.1%, respectively. A higher proportion of LTS underwent surgery n=44 (91,7%), most of them as interval debulking surgery (59.1%). Almost half of STS did not undergo surgery (45,2%), being interval debulking surgery the most frequent systematic approach when surgery was performed (73.9%). Only 9,1% of LTS who underwent surgery had residual disease compared to 27,3% of STS. Harboring mutations in the BRCA1/2 genes is a favorable prognostic factor also associated with chemotherapy sensitivity, in our serires 23% of LTS were BRCA1&2 mutation carriers (11 patients (23%) patients with germline BRCA mutations being 7patients(15%) BRCA1mut and 4patients(8%) BRCA2mut with 4patients(8%) of patients not analyzed). Conclusions: In our cohort, stage III and cytoreduction surgery were more frequent among LTS. Classical clinical characteristics are not enough to identify advanced HGSOC LTS. More investigation on their molecular profile might help to to identify exceptional LTS in order to elucidate better management approaches and new treatments for patients with worse prognosis.

Pilot randomized trial of a telehealth intervention for women with advanced ovarian cancer and PARP inhibitor-related fatigue.

e24122 Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have dramatically changed the treatment of advanced ovarian cancer and are increasingly used in other cancers. However, PARPi cause significant fatigue in nearly half of patients. Psychosocial interventions have shown promise for treating cancer-related fatigue, but there is limited evidence for use in patients with advanced cancers. Moreover, most fatigue interventions have been delivered in person over many sessions, limiting their accessibility and scalability. Methods: We conducted a pilot randomized trial of REVITALIZE, a 6-session telehealth intervention developed and refined by our group, compared with enhanced usual care among 35 fatigued patients with advanced or recurrent ovarian cancer on PARPi at two sites, Dana-Farber Cancer Institute and University of Pennsylvania. REVITALIZE was based on acceptance and commitment-based behavioral therapy and addressed modifiable contributors to PARPi-related fatigue. The trial tested the feasibility, acceptability, and preliminary efficacy of REVITALIZE through 3-month follow-up. Exit interviews were conducted with all REVITALIZE patients. Results: Among 35 participants (mean age=62.5 years, 83% stage III/IV disease, 46% first-line maintenance therapy), the trial met or exceeded its acceptability and feasibility goals. Exit interviews further indicated high acceptability. Relative to enhanced usual care, REVITALIZE significantly reduced fatigue interference at 12-week follow-up (Cohen’s d=.94, p=.008) and fatigue severity (d=.54, p=.049), while improving current fatigue levels (d=.62, p=0.04). REVITALIZE participants also reported improved fatigue self-efficacy, fatigue catastrophizing, depression, anxiety, and quality of life (ds=.60-.86). REVITALIZE participants were also numerically less likely to experience PARPi dose reductions compared with enhanced usual care (7% vs. 17%), and less likely to have dose delays (7% vs. 22%). Conclusions: Among fatigued adults with advanced ovarian cancer on PARPi, a brief telehealth intervention based on acceptance and commitment therapy showed strong feasibility, acceptability, and preliminary efficacy with improvements in fatigue, anxiety, depression, and quality of life outcomes. REVITALIZE is a novel, scalable telehealth intervention worthy of further investigation in patients with advanced cancers with PARPi-related fatigue. The study is supported by the National Comprehensive Cancer Network (NCCN) through a grant provided by AstraZeneca. Neither NCCN or AstraZeneca are the sponsors of this study. Clinical trial information: NCT04525183 .

Real-world data from a multi-center study: Insights to the efficacy and safety in patients with ovarian cancer (OC) received niraparib as first-line (1st-L) maintenance therapy (MT).

5551 Background: Niraparib has significantly extended PFS as 1st-L MT OC in PRIMA/PRIME. Due to the more complex in treatment and status of the patients (pts) in clinal practice, more real-world data is needed to verify the efficacy and safety of Niraparib. Meanwhile, exploring the link between clinical characters and PFS, may to establish a clinical model to predict Niraparib benefits. Methods: This is a retrospective multicentric study recruiting OC pts received Niraparib as 1st-L MT from fourteen hospitals throughout China from Jan. 2019 to Dec. 2021. The database lock-time was on Dec. 31st, 2022. The pts’ basic characters, especially biomarkers, KELIM scores, etc. were recorded. Survival analyses were conducted using the Kaplan-Meier method and log-rank test, and 95% CI were calculated. The primary endpoint was PFS, and secondary endpoints included time to treatment discontinuation (TTD), time to first subsequent therapy (TFST) and safety. The exploratory endpoint was to establish a clinical prediction model of Niraparib benefits. Results: 199 pts’ data were analyzed. The median(m) follow-up at the time of the data cutoff was 14.93 months (mos) (12.17, 39.47). Baseline characteristics were shown in Table. MPFS was not reached (NR) (29.80 to not be estimated, NE), with maturity 29.64%, and PFS rate at 6, 12, 18, 24mos was 89.4%, 79.5%, 68.3%, 64.5% respectively, showing the efficacy of Niraparib. MPFS (95% CI) in subgroups were as follows: BRCAwt 23.83mos (23.83 to NE); HRD negative 15.63mos (12.6 to NE); KELIM＜1 NR (15.33 to NE); BRCA1/2m, HRD positive and KEILM≥1 subgroups were all NR yet, due to the no longer enough follow-up time and low data maturity. Multivariate analysis found that pts with <65 years, BRCA1/2m, HRD positive, KELIM＞1, and R0 after primary cytoreductive surgery were likely to have longer PFS. The rate of grade ≥3 thrombocytopenia was 19.1%. Treatment discontinuation occurred in 11 (5.5%) pts due to TEAEs. The clinical prediction model for probability of progression was established from 149 pts (training dataset): Score = 0.612 Age ＞65 + 0.3889 BMI≤23.90 + 0.097 FIGOIV + 0.191ChronicN +1.398 Surgery resultR1/R2 +2.552 BRCAwt . The probability of disease progression received Niraparib in 6, 12 and 18m can be obtained by mapping the score to the nomogram. Conclusions: The efficacy and safety of Niraparib in this study are consistent with the results in PRIME. The clinical predictive model established in this database needs more data to be matured and verified. [Table: see text]

Efficacy and safety of immune checkpoint inhibitor without pemetrexed for first-line maintenance therapy in advanced lung adenocarcinoma.

e21058 Background: Currently, the standard first-line treatment for driver gene-negative advanced lung adenocarcinoma (LUAD) is chemotherapy plus immune checkpoint inhibitor (ICI) therapy followed by pemetrexed and ICI. However, pemetrexed is prone to certain adverse reactions and needs to be pretreated. At present, there is no relevant study on the efficacy between pemetrexed combined with ICI and ICI monotherapy in maintenance treatment. The object of this study is to explore the efficacy and safety of ICI as maintenance therapy in such patients. Methods: The study retrospectively analyzed patients with driver gene-negative advanced LUAD in PLA General Hospital from January 2019 to June 2022. These patients had received pemetrexed and platinum-based chemotherapy combined with ICI for 4-6 cycles. Patients who didn’t progress were subsequently entered into maintenance stage. The primary endpoint was progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was objective response rate (ORR) and safety. Results: A total of 93 patients with advanced LUAD who received first-line chemotherapy combined with ICI were collected, including 39 patients receiving pemetrexed plus ICI of maintenance therapy, 30 patients receiving ICI maintenance therapy, and 24 patients who failed to enter the maintenance treatment. Baseline characteristics of ICI group and pemetrexed plus ICI group were as follows: median age, 61.5 (42~81) years vs. 63 (35~74) years; male, 66.7% (20/30) vs. 79.5% (31/39); Smoking history, 63.3% (19/30) vs. 74.4% (29/39); Brain metastases, 10% (3/30) vs. 23.1% (9/39). ORR was 60.0% (95%CI 42.5-77.5) in the ICI monotherapy group and 69.2% (95%CI 54.7~83.7) in the pemetrexed plus ICI group. By November 30, 2022, the median follow-up time was 19.2 months. The median PFS of the two groups were 15.8 months (95%CI 9.84-21.70) in ICI group and 22.8 months (95%CI 4.57-40.97) in pemetrexed plus ICI group and there was no statistical difference between the two groups (P = 0.50). Neither group achieved OS. The incidence of all grade treatment-related adverse events (TRAEs) was 90.0% (27/30) in ICI monotherapy group and 92.3% (36/39) in pemetrexed plus ICI group. Grade 3/4 TRAEs occurred in 23.3% (7/30) and 23.1% (9/39) of each cohort and no grade 5 TRAE occurred. Conclusions: ICI maintenance therapy without pemetrexed showed great therapeutic efficacy in first-line maintenance stage and can be a feasible regimen in advanced lung adenocarcinoma.

HRD effects on first-line adjuvant chemotherapy and PARPi maintenance therapy in Chinese ovarian cancer patients

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large retrospectively collected Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526–0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423–0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs. 12 months; HR, 0.438; 95% CI, 0.201–0.957; P = 0.033) and OS (median, NA vs. NA months; HR, 0.12; 95% CI, 0.029–0.505; P = 0.001). Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial

BackgroundIn the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries. ObjectiveTo analyze clinically relevant subgroups from JAVELIN Bladder 100. Design, setting, and participantsPatients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). Median follow-up was >19 mo in both arms (data cutoff October 21, 2019). This trial is registered on ClinicalTrials.gov as NCT02603432. Outcome measurements and statistical analysisOS (primary endpoint) and PFS were analyzed in protocol-specified and post hoc subgroups using the Kaplan-Meier method and Cox proportional hazards models. Results and limitationsHazard ratios (HRs) for OS with avelumab + BSC versus BSC alone were <1.0 across all subgroups examined, including patients treated with 1L cisplatin + gemcitabine (HR 0.69, 95% confidence interval [CI] 0.50–0.93) or carboplatin + gemcitabine (HR 0.64, 95% CI 0.46–0.90), patients with PD-L1+ tumors treated with carboplatin + gemcitabine (HR 0.67, 95% CI 0.39–1.14), and patients whose best response to chemotherapy was a complete response (HR 0.80, 95% CI 0.46–1.37), partial response (HR 0.62, 95% CI 0.46–0.84), or stable disease (HR 0.70, 95% CI 0.46–1.06). Observations were similar for PFS. Limitations include the smaller size and post hoc evaluation without multiplicity adjustment for some subgroups. ConclusionsAnalyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy. Patient summaryIn the JAVELIN Bladder 100 study, maintenance treatment with avelumab helped many different groups of people with advanced cancer of the urinary tract to live longer.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N=733) were initially treated with a fixed starting dose (FSD) regimen of 300mg every day. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200mg every day in patients with baseline body weight<77kg or baseline platelet count<150,000/µL, and 300mg every day in all other patients. Efficacy and safety outcomes were assessed by starting dose. Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n=317; placebo, n=158) and 258 (35.2%) were assigned to an ISD (niraparib, n=170; placebo, n=88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

5-aminosalicylate maintenance is not superior to no maintenance in patients with newly diagnosed Crohn's disease-A nationwide cohort study.

5-aminosalicylates (5-ASA) are widely used in Crohn's disease (CD) despite guidelines advising otherwise. We aimed to assess in nationwide study the outcomes of first-line 5-ASA maintenance therapy (5-ASA-MT) compared with no maintenance treatment (no-MT) in patients with newly diagnosed CD. We utilised data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel between 2005 and 2020. Propensity score (PS) matching was utilised to compare outcomes in the 5-ASA-MT versus no-MT groups. Of the 19,264 patients diagnosed with CD, 8610 (45%) fulfilled the eligibility criteria (3027 [16%] received 5-ASA-MT and 5583 [29%] received no-MT). Both strategies declined over the years; 5-ASA-MT from 21% of CD patients diagnosed in 2005 to 11% in 2019 (p < 0.001) and no-MT from 36% to 23% (p < 0.001). The probability of maintaining therapy at 1, 3 and 5 years from diagnosis: 5-ASA-MT-78%, 57% and 47% and no-MT-76%, 49% and 38% respectively (p < 0.001). PS analysis successfully matched 1993 pairs of treated and untreated patients and demonstrated comparable outcomes of time to: biologic (p=0.2), steroid dependency (p=0.9), hospitalisation (p=0.5) and CD-related surgery (p=0.1). Rates of acute kidney injury (5.2% vs. 3.3%; p < 0.001) and pancreatitis (2.4% vs. 1.8%; p=0.03) were higher in the 5-ASA-MT group compared with the no-MT group but after PS matching the rates of adverse events were similar. First-line 5-ASA monotherapy was not superior to no-MT but associated with a slightly higher rates of adverse events, while both strategies have declined over the years. These findings suggest that a subset of patients with mild CD may be offered a watchful waiting approach.

Avelumab First-Line Maintenance Treatment in Advanced Bladder Cancer: Practical Implementation Steps for Infusion Nurses

The immune checkpoint inhibitor avelumab was approved as first-line maintenance treatment for patients with advanced urothelial carcinoma (UC) that has not progressed on first-line platinum-containing chemotherapy. The approval was based on data from the phase 3 JAVELIN Bladder 100 trial. Avelumab first-line maintenance is now considered the standard-of-care treatment for this patient group. Infusion nurses are at the front line of patient care and play a vital role throughout the treatment journey of patients with advanced UC. In this video, based on the publication ‘Avelumab First-Line Maintenance Treatment in Advanced Bladder Cancer: Practical Implementation Steps for Infusion Nurses’, Dawn Conway (University of Chicago Medicine, IL, USA) reviews key considerations related to avelumab first-line maintenance therapy that infusion nurses should be familiar with. These include dosing, administration, and immune-related adverse event recognition and management, to ensure safe and appropriate use of this important and impactful therapy.

A Review of the Latest Advancements in Ovarian Cancer Care Featured at ESMO 2022

Ovarian cancer is the seventh most commonly diagnosed cancer among females and the most lethal gynaecologic malignancy globally because of its vague presentation, insidious nature, recurrence, and drug resistance. There is a pressing need to improve survival and quality of life in patients with ovarian cancer in the context of rising global incidence, high risk of relapse, and poor prognosis. Presentations at the European Society for Medical Oncology (ESMO) Congress 2022 from 9th–13th September in Paris, France, showed the breadth and depth of research in ovarian cancer, including a first look at the highly anticipated data from Phase III studies on the impact on overall survival (OS) of poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy. Clinically meaningful OS benefit was shown with olaparib at 5 years’ follow-up in PAOLA-1 and at 7 years’ follow-up in SOLO1. These positive results are a breakthrough in ovarian cancer treatment and are an important indicator that improvements in progression-free survival (PFS) may translate into OS benefits. Studies in which PARP inhibitors showed clinically meaningful efficacy, but OS data remain immature, include PRIMA, in which niraparib as a first-line maintenance therapy maintained clinically significant improvement in progression-free survival at 3.5 years’ follow-up. Research into chemotherapy resistance using a glucocorticoid receptor modulator in combination with nab-paclitaxel as part of second-line treatment showed that glucocorticoid receptor modulation can improve the efficacy of chemotherapy. Pre-clinical and early phase clinical studies are investigating a range of approaches for the treatment of ovarian cancer such as development of a chimeric antigen receptor T cell therapy, combination of a PARP inhibitor and an immune checkpoint inhibitor, and a bispecific antibody. Developments in these areas are awaited with interest. There is considerable focus on biomarkers for prognosis and progression in ovarian cancer, including research on breast related cancer antigen and homologous recombination deficiency testing, cancer antigen 125 (CA125) decline, and circulating tumour DNA (ctDNA); however, wider genetic testing, improved education of physicians on the importance of testing, and increased access to testing are recommended to optimise treatment and disease prevention. The research in ovarian cancer presented at ESMO 2022 marks important progress in this field.

33O PRIMA/ENGOT-OV26/GOG-3012 study: Long-term conditional PFS

Niraparib (nir) showed a blinded independent central review–assessed PFS benefit as a first-line (1L) maintenance therapy (MT) in the primary analysis of PRIMA (data cut 17 May 2019) across biomarker subgroups, including a substantial benefit in patients (pts) with homologous recombination–deficient (HRd) tumours. These results were the basis for approval of nir as MT after response to 1L platinum-based chemotherapy (CT). Here we report investigator-assessed (IA) cPFS (the probability of remaining alive and progression free beyond a specified landmark) in PRIMA. This double-blind, placebo (PBO)-controlled phase 3 trial evaluated nir in pts with newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer (OC) at high risk for relapse after a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to 1L CT regimen (CR/PR), receipt of neoadjuvant CT (yes/no), and homologous recombination deficiency status (HRd or HRp/HRnd) per the Myriad myChoice® CDx PLUS assay. Pts received nir or PBO once daily (2:1 ratio). IA cPFS was analysed for the HRd and intention-to-treat (ITT) populations, using the 17 Nov 2021 data cut. The median follow-up time was 3.5 y. The estimated PFS rate at 4 y was 38% for nir-treated pts and 17% for PBO-treated pts in the HRd population and 24% (nir) vs 14% (PBO) in the ITT population. The 2-y cPFS probabilities beyond the 1- and 2-y landmarks were higher in the nir arm than in the PBO arm (HRd: 1 y: 62% vs 50%, 2 y: 74% vs 60%; ITT: 1 y: 54% vs 46%, 2 y: 67% vs 64%). Safety was previously reported (González-Martín, et al. Ann Oncol. 2022;33[suppl 7]:S789). A durable PFS benefit (nir vs PBO) was observed up to 4 y after randomisation in the ITT and HRd populations, as determined by IA. Pts free from disease progression or death at the 2-y landmark had a high probability of remaining free from progression or death at 4 y, supporting the use of nir as a 1L MT.Table: 33OHRdNirPBOLandmark time from randomizationEvents/total pts2-y probability from landmark, % (95% CI)Events/total pts2-y probability from landmark, % (95% CI)0137/24751 (44–57)98/12629 (21–37)1 y69/15962 (54–70)33/5750 (36–62)2 y26/11074 (64–82)11/3460aITTLandmark time from randomizationNirPBOEvents/total pts2-y probability from landmark, % (95% CI)Events/total pts2-y probability from landmark, % (95% CI)0332/48736 (31–40)199/24622 (17–28)1 y124/24454 (47–60)54/9246 (36–56)2 y42/15267 (57–76)15/5164aa95% CI were not calculated at time points with <10 pts. Open table in a new tab

Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake.

Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.

Real-world clinical data analysis of PARPi as first-line maintenance therapy in newly diagnosed epithelial ovarian cancer patients

Objective: The real-world clinical data of patients with newly diagnosed ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) who received first-line maintenance therapy with poly adenosine diphosphate ribose polymerase inhibitor (PARPi) were retrospectively analyzed, and the prognostic factors were preliminarily explored. Methods: (1) The clinicopathological data and follow-up data of ovarian cancer patients treated with PARPi first-line maintenance therapy from August 2018 (PARPi was launched in China) to December 31, 2021 in Sichuan Cancer Hospital were collected (real-world clinical data). (2) According to the different types of PARPi, real-world clinical data were divided into olaparib group and niraparib group, which were respectively compared with the inclusion and exclusion criteria of representative domestic and foreign phase Ⅲ randomized controlled trials (RCT), including olaparib as first-line maintenance therapy for advanced ovarian cancer patients with BRCA1/2 gene mutation (SOLO-1 study), niraparib as first-line maintenance therapy (PRIMA study), and niraparib as first-line maintenance therapy for Chinese advanced ovarian cancer patients (PRIME study). (3) The prognosis of the two groups and the prognostic factors were analyzed. Results: (1) A total of 83 patients were included in this study, with a median age of 51 years (47-57 years), including 75 cases of ovarian cancer, 5 cases of fallopian tube cancer, and 3 cases of primary peritoneal cancer; 5 cases of stage Ⅰ, 9 cases of stage Ⅱ, 55 cases of stage Ⅲ, 12 cases of stage Ⅳ, and 2 cases of unknown stage; neoadjuvant chemotherapy (NACT) was performed in 40 cases and non-NACT in 43 cases; 62 cases had no visible residual lesion after surgery (R0), 9 cases had residual disease lesions <1 cm (R1), 8 cases had residual disease lesions ≥1 cm (R2), and 4 cases with unknown postoperative residual disease. Thirty-two cases had PARPi treatment interruption, 40 cases had PARPi reduction, and 1 case terminated treatment due to acute leukemia. Of the 83 patients, 35 were in the olaparib group and 48 were in the niraparib group. The proportion of patients with high-grade serous carcinoma (100% and 75%, respectively) and the proportion of BRCA mutant patients (91% and 10%, respectively) in the olaparib group were higher than those in the niraparib group (all P<0.01). (2) Compared with the inclusion and exclusion criteria of the SOLO-1 study, the olaparib group had only 60% (21/35) coincidence rate; compared with the inclusion and exclusion criteria of PRIMA and PRIME studies, the coincidence rates of niraparib group were only 31% (15/48) and 69% (33/48). The most common reasons for non-compliance were number of chemotherapy courses, histopathological type, and surgical pathological stage. (3) Of the 83 cases received first-line maintenance therapy with PARPi, the median follow-up was 15.9 months (11.3-22.9 months), the median progression-free survival (PFS) was 29.7 months (95%CI: 25.9-33.6 months), and the median overall survival was 49.8 months (95%CI: 47.4-52.2 months). Univariate analysis showed that unilateral or bilateral ovarian cancer, efficacy after platinum-containing chemotherapy, presence or absence of measurable lesions at the end of chemotherapy, and total number of chemotherapy courses were significantly associated with PFS (all P<0.05). Multivariate analysis showed that unilateral or bilateral ovarian cancer, total number of chemotherapy courses, and efficacy after platinum-containing chemotherapy were independent factors affecting PFS in stage Ⅱ-Ⅳ patients with PARPi first-line maintenance therapy (all P<0.05). Conclusions: Unilateral ovarian cancer, the total number of chemotherapy courses no more than 9, and achieving complete response after platinum-containing chemotherapy before maintenance therapy are independent influencing factors of PFS benefit in patients with PARPi first-line maintenance therapy. Due to the large differences between the patients in real clinical practice and the research subjects of phase Ⅲ RCT, the results of representative retrospective studies still have important clinical reference significance.

575P Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade serous or endometrioid ovarian cancer: A multi-national observational study

Maintenance therapy with a poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi) improves survival outcomes in women with high-grade serous or endometroid ovarian cancer (HGS/EOC) whose disease responds to platinum-taxane chemotherapy, with the greatest benefit reported in BRCA-mutant/Homologous Recombination Deficient (HRD)-tumours. We report the prevalence of BRCA-mutant/HRD-tumours in women with newly diagnosed FIGO stage III/IV HGS/EOC in England, Wales and Northern Ireland between April 2021 and April 2022. These data represent the first year that routine HRD testing was available through the NHS. Eligibility criteria included newly diagnosed FIGO stage III/IV HGS/EOC. The Myriad myChoice® HRD assay was used to detect pathogenic BRCA1/2 variants and a genomic instability score (GIS) in formalin-fixed paraffin-embedded tumour tissue. Testing was performed during standard-of-care first-line therapy pathways. All patients gave informed consent for tumour testing. No cases were included that were tested as part of a clinical trial. Testing was co-ordinated by the NHS Genomic Hub Laboratory network. Tumour BRCA1/2 and GIS testing was requested for 2,829 patients. 2,474 (87.5%) and 2,178 (77.0%) patients were successfully tested for BRCA1/2 or GIS, respectively. 385 (15.6%) BRCA1/2 pathogenic variants were detected (BRCA1=220; BRCA2=165). The GIS was ≥42 in 814 (37.4%) patients. 510 (23.4%) patients had tumour BRCA1/2 wild-type and a GIS ≥42. GIS had a bimodal distribution, with BRCA1/2-mutant tumours having higher scores than wild-type tumours. In this study of women with newly diagnosed FIGO stage III/IV HGS/EOC, 895 (36.2%) were found to have a BRCA1/2 mutation and/or a GIS ≥42, and therefore had the opportunity to benefit from first-line PARPi maintenance therapy. This is the largest real-world evidence cohort for the prevalence of HRD-tumours in HGS/EOC. These data highlight the importance of HRD testing to optimise outcomes for eligible women. The rapid uptake of HRD testing in England, Wales and Northern Ireland also demonstrates the power of centralised NHS funding, centre specialisation and the Genomic Hub Laboratory network.

530P PRIMA/ENGOT-OV26/GOG-3012 study: Updated long-term PFS and safety

Niraparib (nir) has shown PFS benefit as a first-line (1L) maintenance therapy (MT) in the PRIMA primary analysis (data cut 17 May 2019) in all subgroups regardless of biomarker status. These results were the basis for approval of nir as MT after response to 1L platinum-based chemo (CT). Here we report updated long-term efficacy and safety in the PRIMA study.

Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitor first-line maintenance among patients with newly diagnosed advanced ovarian cancer in a real-world database (351)

Objectives: With the advent of poly (adenosine diphosphate [ADP]- ribose) polymerase inhibitors (PARPi), first-line (1L) maintenance therapy in patients with ovarian cancer (OC) has evolved in recent years. This study described the use of 1L maintenance and assessed predictors of 1L PARPi maintenance therapy use among PARPi- eligible patients with OC in a real-world setting. Methods: This retrospective cohort study included patients with newly diagnosed stage III/IV epithelial OC who received the last dose of 1L platinum-based chemotherapy (PBC) between January 1, 2017, and February 28, 2021, from the nationwide Flatiron Health electronic health record-derived database. During the study period, the de-identified data originated from approximately 280 US cancer clinics. The end of the last cycle of 1L PBC was defined as the index date. Patients who started a second-line treatment within two months of the index date were excluded. Multivariable logistic regression was used to identify predictors of 1L PARPi monotherapy use versus active surveillance (AS). Variables included in the model were selected using the stepwise approach. Results: A total of 1010 patients were included in the study; 37.9% and 62.1% of patients received maintenance therapy and AS, respectively. A total of 162 (16.0%) patients received PARPi monotherapies (niraparib 6.3%, olaparib 8.7%, and rucaparib 1.0%), 122 (12.1%) received bevacizumab monotherapy, 33 (3.3%) received bevacizumab + PARPi combination therapies and 66 (6.5%) received other therapies. The median age was 68.0 years (Q1:58.0; Q3:75.0) for AS and 65.0 years (56.0; 71.8) for PARPi monotherapies. Other patient characteristics are shown in Table 1. Patients with BRCA mutation were significantly more likely to receive PARPi monotherapies (odds ratio [OR]: 7.49; 95% CI: 4.21-13.31) than patients with BRCA wild-type. Patients treated in 2019 (OR: 7.57; 95% CI: 3.86-14.86) and 2020 (OR: 14.99; 95% CI: 7.61-29.53) were significantly more likely to receive PARPi monotherapies than patients treated in 2017. Race, region of residence, practice type, FIGO stage at initial diagnosis, Eastern Cooperative Oncology Group (ECOG) score, residual disease status, and other disease characteristics were not selected into the model. Conclusions: Over the last four years, the use of 1L PARPi maintenance among ovarian cancer patients has increased significantly, mostly driven by biomarker status. However, stage and extent of residual disease after surgery were not associated with PARPi maintenance use. Objectives: With the advent of poly (adenosine diphosphate [ADP]- ribose) polymerase inhibitors (PARPi), first-line (1L) maintenance therapy in patients with ovarian cancer (OC) has evolved in recent years. This study described the use of 1L maintenance and assessed predictors of 1L PARPi maintenance therapy use among PARPi- eligible patients with OC in a real-world setting. Methods: This retrospective cohort study included patients with newly diagnosed stage III/IV epithelial OC who received the last dose of 1L platinum-based chemotherapy (PBC) between January 1, 2017, and February 28, 2021, from the nationwide Flatiron Health electronic health record-derived database. During the study period, the de-identified data originated from approximately 280 US cancer clinics. The end of the last cycle of 1L PBC was defined as the index date. Patients who started a second-line treatment within two months of the index date were excluded. Multivariable logistic regression was used to identify predictors of 1L PARPi monotherapy use versus active surveillance (AS). Variables included in the model were selected using the stepwise approach. Results: A total of 1010 patients were included in the study; 37.9% and 62.1% of patients received maintenance therapy and AS, respectively. A total of 162 (16.0%) patients received PARPi monotherapies (niraparib 6.3%, olaparib 8.7%, and rucaparib 1.0%), 122 (12.1%) received bevacizumab monotherapy, 33 (3.3%) received bevacizumab + PARPi combination therapies and 66 (6.5%) received other therapies. The median age was 68.0 years (Q1:58.0; Q3:75.0) for AS and 65.0 years (56.0; 71.8) for PARPi monotherapies. Other patient characteristics are shown in Table 1. Patients with BRCA mutation were significantly more likely to receive PARPi monotherapies (odds ratio [OR]: 7.49; 95% CI: 4.21-13.31) than patients with BRCA wild-type. Patients treated in 2019 (OR: 7.57; 95% CI: 3.86-14.86) and 2020 (OR: 14.99; 95% CI: 7.61-29.53) were significantly more likely to receive PARPi monotherapies than patients treated in 2017. Race, region of residence, practice type, FIGO stage at initial diagnosis, Eastern Cooperative Oncology Group (ECOG) score, residual disease status, and other disease characteristics were not selected into the model. Conclusions: Over the last four years, the use of 1L PARPi maintenance among ovarian cancer patients has increased significantly, mostly driven by biomarker status. However, stage and extent of residual disease after surgery were not associated with PARPi maintenance use.

Niraparib treatment for patients with BRCA-mutated ovarian cancer: review of clinical data and therapeutic context.

We reviewed clinical data for niraparib monotherapy in BRCA-mutated (BRCAm) epithelial ovarian cancer (OC), contextualizing results with data from other poly(ADP-ribose) polymerase inhibitors (PARPis). Niraparib reduced the likelihood of progression or death by 60% as first-line maintenance therapyand by 73-78% in recurrent disease. In heavily pretreated OC, efficacy was greater in the BRCAm versus non-BRCAm cohort. Quality-of-life (QoL) was maintained throughout treatment. Adverse eventswere consistent with the known niraparib safety profile. Cumulative efficacy, safety and QoL evidence demonstrate niraparib maintenance monotherapy has a positive benefit:risk ratio in BRCAm OC. Niraparib significantly improved progression-free survival as first-line maintenance therapy in all patients with OC (i.e., of any biomarker status).

P917: HOW COMORBID ARE OUR MYELOMA PATIENTS AND HOW MANY MAKE IT TO THE SECOND-LINE TREATMENT: REAL-WORLD DATA OF 251 MYELOMA PATIENTS TREATED IN THE HEMATOLOGICAL NETWORK OF THE OEGK

Background: Comorbid conditions have a negative impact on overall survival (OS) in multiple myeloma (MM) patients. Furthermore, a European multi-center study reported that only 61% of patients proceed to second-line treatment. Aims: The objective of this study was to determine the prevalence of common comorbidities and their impact on OS. Furthermore, we examined the mortality during first-line treatment and the percentage of patients proceeding to second-line treatment. Methods: This retrospective study was conducted in the hematology care network “Hämatologieverbund der Österreichischen Gesundheitskasse (OEGK)”, consisting of the Hanusch hospital and three outpatient centers, in Vienna, Austria. We included all patients who were observed and/or treated for multiple myeloma between 2012 and 2018 within the hematology care network. Follow-up was conducted until March 2021. Results: We analyzed 251 patients (median age 69 years). Prevalent concomitant conditions at diagnosis were hypertension (67.4%), further cardiovascular diseases excluding hypertension (23.1%), obesity (15.2%), diabetes (13.8%) and chronic lung disease (9.2%). For the evaluation of renal impairment, we used the CCI, which defines kidney disease as a creatinine >3mg/dl or the need for dialysis, as well as the chronic kidney disease (CKD) classification system. While 7.8% of patients fulfilled the CCI criteria for kidney disease, 39.5% had a CKD stage ≥3A. Comorbidity in general, as well as specific comorbid conditions had a negative effect on overall survival. Patients with a CCI score of 0 points at diagnosis showed a median OS of 8.7 years compared to 3.8 years and 2.6 years for patients with a score of 1 point and ≥2 points, respectively (p <0.001). We also observed a reduced OS of 4.9 years in patients with at least one creatinine clearance (CrCl) value <60 ml/min throughout the observation period compared to 16.4 years in patients with a CrCl consistently ≥60 ml/min (p <0.001). In total, 232 patients received a first-line treatment. During the observation period after first-line therapy, 146 patients proceeded to second-line treatment due to progress, 30 showed no sign of progress so far and 12 had an ongoing first-line maintenance therapy. 21 patients were referred from other centers for a second opinion and/or ASCT. These patients were still alive at the end of the observation period, but data about further treatment lines were missing. One patient eligible for second-line treatment refused further therapeutic measures. Furthermore, 22 patients died during first-line treatment or the subsequent treatment-free interval. Of these 22 patients, 11 died during active first-line treatment due to progression of myeloma or treatment-related toxicity. The other 11 patients died after completion of first-line treatment during the observation period due to secondary neoplasms (4) and infection (2). For the remaining five patients the cause of death was unknown. In total, 90.5% of patients who had received a first-line treatment were or still are eligible for second-line treatment. Summary/Conclusion: Comorbid conditions were prevalent in our population and exerted a major impact on mortality. In comparison to the CCI, the chronic kidney disease classification system showed superior sensitivity for detection of renal impairment, which is a good predictor of survival. In contrast to previously published data, a high proportion of patients were eligible for second-line treatment. Disease-specific mortality prevented only a small number of patients from receiving second-line treatment.

Efficacy and Safety of Anlotinib in the Treatment of Small Cell Lung Cancer: A Real-World Observation Study.

AimsThis study aimed to observe the efficacy and safety of anlotinib in the treatment of small cell lung cancer (SCLC) in the real world, as first-line maintenance therapy, second-line, and above.MethodsClinical data of 109 patients with SCLC treated with anlotinib and hospitalized at The First Affiliated Hospital of Zhengzhou University from June 2018 to June 2020 were retrospectively analyzed. Analysis of short-term efficacy and survival was performed, with p<0.05 being considered statistically significant.ResultsThe median progression-free survival (mPFS) of anlotinib monotherapy used as first-line maintenance treatment of SCLC was 6.3 months (11.7 months in the limited phase and 5.8 months in the extensive phase) and median overall survival (mOS) was 16.7 months (not reached in limited phase, 12.6 months in extensive phase). In second-line treatment, anlotinib with chemotherapy prolonged PFS and OS as compared to anlotinib monotherapy (p<0.05). In third-line and above treatment, there was no improvement in mPFS with the chemotherapy combination regimen compared to anlotinib monotherapy (3.6 months vs. 3.8 months, p=0.398), with a trend toward impaired mOS (8.5 months vs. not achieved, p=0.060). Univariate analyses and multivariate analyses revealed that Eastern Cooperative Oncology Group performance status and liver metastases were independent prognostic factors affecting PFS and OS. No new anlotinib-related adverse reactions were identified.ConclusionAnlotinib was effective for first-line maintenance and second-line treatment, and the chemotherapy combination regimen was superior to monotherapy when applied as second-line treatment. However, this trend was not observed in third-line and above therapy.