1L Setting Research Articles

Quality of life in patients with advanced high-grade ovarian cancer (HGOC) receiving maintenance therapies after first-line (1L) chemotherapy in the randomized phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644).

5560 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, maintenance olaparib + bevacizumab (bev) provided a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with newly diagnosed advanced ovarian cancer in response to platinum-based chemotherapy. Subgroup analyses revealed a substantial PFS benefit in homologous recombination deficiency (HRD)-positive (including BRCA1/2 mutation) pts, leading to US/EU labels for this combination. Preliminary analyses reported that olaparib did not alter global health-related quality of life (G-HQoL; Ray-Coquard I et al. NEJM 2019). We analyzed HQoL by domains and molecular subgroups and explored the impact of disease progression (DP) on HQoL in the 1L setting. Methods: Eligible pts with newly diagnosed advanced (FIGO stage III–IV) HGOC were randomized 2:1 to maintenance olaparib + bev or pbo + bev. Pts completed European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 HQoL questionnaires at baseline and every 12 weeks for 2 years’ follow-up, irrespective of DP. The minimal important difference for clinically relevant change was fixed at 10 points. Longitudinal data were analyzed by mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD). Analyses were in the intent-to-treat population and HRD-positive subgroup. HQoL analyses at DP (± 60 days) were explored. Results: 806 pts were randomized to olaparib + bev (n=537) or pbo + bev (n=269). 465 pts had DP over 2 years’ follow-up. Compliance to HQoL questionnaires was high at baseline (95%) and over time (>70%). MMRM models by HQoL domain did not reveal a clinically relevant difference between treatment arms over time. TUDD of G-HQoL did not differ between arms (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.72–1.07). In the HRD-positive subgroup (n=372), we observed no difference by HQoL domain between treatment arms. Interestingly, TUDD of G-HQoL was statistically significantly in favor of olaparib + bev compared with pbo + bev (HR 0.70, 95% CI 0.52–0.93). We also observed a clinically significant deterioration in emotional (mean change −12.30 points, 95% CI −16.46 to −8.13) and social (−11.17 points, 95% CI −16.21 to −6.12) functioning in both treatment arms at DP, among 103 pts with HQoL questionnaires at DP. Conclusions: The substantial PFS benefit provided by maintenance olaparib + bev in the newly diagnosed setting was achieved without detrimental effect on HQoL domains, even with longer TUDD of G-HQoL in the HRD-positive subgroup. Use of an effective maintenance therapy (ie one with a significant PFS benefit) in HGOC patients in the 1L setting is likely to delay the clinically significant deterioration in emotional and social functioning we identified in patients at DP across PAOLA-1 treatments arms. Clinical trial information: NCT02477644.

Real-world use of PD-(L)1 immune checkpoint inhibitors (CPI) and post-CPI treatment patterns and outcomes in ovarian and endometrial cancer (2014-2021).

e18795 Background: Given the rapid adoption of immune checkpoint inhibitors (CPI) in gyn cancers, we sought to characterize the real-world (RW) use of CPI, treatment patterns post-CPI, and clinical outcomes of patients (pts) with ovarian (OC) or endometrial (EC) cancer in the US. Methods: A retrospective analysis of pts with OC/EC treated with ≥1 line of systemic therapy after 1/1/2014 within the Flatiron Health (FH) real-world data (RWD) Electronic Health Record (EHR) was conducted. FH is a longitudinal EHR-derived de-identified database from ̃280 US cancer clinics. Treatment patterns after 1st CPI were identified and analyzed in pts with ≥ 6 months of observation from starting CPI per the EHR. Descriptive comparisons were performed using χ2 or t-tests, as appropriate. Time-to-next treatment (i.e., time from starting initial CPI to 1st subsequent therapy post-CPI/death) served as a PFS proxy. Pre-specified survival analyses via Kaplan-Meier methods were used for CPI therapy (i.e., 1L, 2L, 3L) and class of post-CPI therapy. Results: 7639 pts (5415 OC, 2224 EC) received ≥1 line of therapy. Median age was 65 [57-73] (OC) and 66 [60-72] (EC); 67% were white; 84% were in community practices; 34% had commercial insurance; 69% OC and 59% EC had Stage III/IV disease; 10% OC had a BRCA1/2 mutation; 12% EC were MSI-H/dMMR. 130 (2.4%) OC pts and 326 (14.7%) EC pts received CPI at any point of their cancer care. Among pts receiving CPI, CPI was given as 1st, 2nd, and ≥3rd line of therapy in 13.8%, 18.5%, 67.7% of OC pts, and 24.6%, 32.5%, 42.9% of EC pts. Median time-to-next treatment for OC pts on CPI was 5.52, 4.60, and 4.04 months in the 1L, 2L, and 3L setting, respectively (p=0.98), and for EC pts, 9.23, 6.41, and 4.27 months in the 1L, 2L, and 3L setting, respectively (p=0.05). 68 (52.3%) OC pts received subsequent therapy post-CPI; 39 (30.0%) died < 90 days post-CPI; 4 (3.1%) died > 90 days post-CPI, and 19 (14.6%) were alive with no evidence of subsequent therapy. In contrast, 110 (33.7%) of EC pts received subsequent therapy post-CPI; 98 (30.0%) died < 90 days post-CPI; 9 (2.8%) died > 90 days post-CPI, and 105 (32.2%) were alive with no evidence of subsequent therapy. Of 68 OC pts who received subsequent therapy after CPI, 38.2% received chemo only, 25.0% additional CPI (alone or in combo), 16.2% targeted therapy, and 14.7% chemo + bevacizumab. Of 110 EC pts who received subsequent therapy, 38.2% received chemo only, 29.1% additional CPI (alone or in combo), 20.0% targeted therapy, and 6.4% chemo + bevacizumab. Conclusions: Checkpoint inhibitors were used in later lines of therapy more notably in OC than EC. Time-to-next treatment on CPI did not seem to vary by line of therapy among OC pts, whereas time-to-next treatment on CPI appeared longer when CPI was used earlier among EC pts. This study reveals early observations into the RW use and sequencing of checkpoint inhibitors in ovarian and endometrial cancers.

Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.

107 Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses <1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses <1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]

Quality of life (QOL) with ribociclib (RIB) plus aromatase inhibitor (AI) versus abemaciclib (ABE) plus AI as first-line (1L) treatment (tx) of hormone receptor-positive/human epidermal growth factor receptor–negative (HR+/HER2−) advanced breast cancer (ABC), assessed via matching-adjusted indirect comparison (MAIC).

1015 Background: The combination of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + endocrine therapy is the recommended 1L tx for HR+/HER2− ABC. A statistically significant overall survival (OS) benefit with RIB + AI was recently reported for MONALEESA-2 (ML-2); final OS results for the MONARCH 3 (MON-3) trial of ABE + AI are pending. QoL is an important end point that affects tx decisions. Understanding the impact of CDK4/6i on QoL is of increasing importance given use in earlier tx lines for ABC and an emerging role in treating early breast cancer, where QoL considerations may be more relevant. MAIC analysis allows for comparative effectiveness in the absence of head-to-head trial data. In this analysis, patient (pt)-reported QoL for the Phase III ML-2 (RIB + AI) and MON-3 (ABE + AI) trials were compared using MAIC with a focus on individual domains; the PALOMA-2 trial could not be considered for this analysis because of the different pt-reported outcome measures evaluated in the trial compared to ML-2 and MON-3. Methods: An anchored MAIC of QoL with RIB + AI vs ABE + AI was performed using data from EORTC QLQ-C30 and BR-23 questionnaires, individual participant data from ML-2 (data cutoff: 6/10/2021), and published data from MON-3 (data cutoff: 11/3/2017). All available QoL data were used in this analysis; the median follow-up for ML-2 was 79.7 months, and the median duration of follow-up at which QoL data were reported for MON-3 was 26.73 months. Inclusion and exclusion criteria were generally similar. Pts in both arms of ML-2 were weighted to match baseline characteristics in the corresponding arms of MON-3. Cox proportional hazards model was used to generate hazard ratios (HRs); anchored HRs were calculated using the Bucher method. Time to sustained deterioration (TTSD) was calculated as the time from randomization to a ≥ 10-point deterioration with no later improvement above this threshold. Results: 205 and 149 pts from the ML-2 arms of RIB/PBO were matched to 328 and 165 pts from the ABE/PBO arms of MON-3. After weighting, pt characteristics were well balanced. TTSD significantly favored RIB vs ABE in appetite loss (HR, 0.46; 95% CI, 0.27-0.81), diarrhea (HR, 0.42; 95% CI, 0.23-0.79), and fatigue (HR, 0.63; 95% CI, 0.41-0.96) as measured by QLQ-C30 and arm symptoms (HR, 0.49; 95% CI, 0.30-0.79) as assessed by BR-23. TTSD did not significantly favor ABE vs RIB in any functional or symptom scale of the QLQ-C30 or BR-23. Conclusions: This MAIC suggests that RIB + AI is associated with better symptom-related QoL vs ABE + AI for postmenopausal pts with HR+/HER2− ABC in the 1L setting. QoL differences between CDK4/6i and their associated adverse event profiles may impact clinical decisions in HR+/HER2− ABC.

Real-world (RW) treatment patterns and clinical outcomes for chemotherapy-based regimens in first line (1L) MSI-H/dMMR metastatic colorectal cancer (mCRC).

e18755 Background: Until the global approval of pembrolizumab for the treatment of first line (1L) MSI-H/dMMR metastatic CRC (mCRC), newly diagnosed patients were managed with standard of care (SOC) treatments like chemotherapy with or without an EGFR/VEGF inhibitor, independent of biomarker testing or status. This study assessed the RW SOC treatment patterns and outcomes among 1L MSI-H/dMMR mCRC patients. Methods: A retrospective observational study was conducted among patients ≥18 years diagnosed with stage IV MSI-H/dMMR mCRC (index event) who received care in the US community-based Oncology Network. Eligible patients were identified between 01-Jun-2017 to 29-Feb-2020 and followed longitudinally until 31-Aug-2020, last patient record, or date of death: whichever occurred first. Baseline demographics, clinical characteristics, treatment patterns and clinical outcomes were reported descriptively. Key clinical outcomes of interest were time to treatment discontinuation (TTD), rw-progression free survival (rwPFS) and overall survival (OS). Kaplan-Meier survival analysis was conducted for all time-to-event variables. Results: 150 MSI-H/dMMR CRC patients treated in the 1L setting were included, of which 38.7% were treated with chemotherapy and 61.3% with chemotherapy + an EGFR/VEGF inhibitor. Nearly 75% of patients had an ECOG PS of 0-1, and the time from diagnosis of metastatic disease to initiation of 1L treatment was 5.2 (0.1, 1157.4) weeks. The median duration of follow-up was 12.9 (0.1, 37.1) and 16.2 (0.8, 36.2) months among patients treated with chemotherapy and chemotherapy + EGFR/VEGF inhibitors, respectively. Within the chemotherapy group, 86% received FOLFOX while 14% received FOLFIRI. Within the chemotherapy + EGFR/VEGF group, the most common regimen was FOLFOX+bevacizumab (67%). Conclusions: The totality of RW clinical outcomes in 1L MSI-h/dMMR mCRC suggest that despite the availability of chemotherapy and EGFR/VEGF inhibitors, an unmet need still exists that may be addressed with the recent availability of pembrolizumab for select patients. This data further supports the rationale for biomarker testing and personalized treatment of 1L CRC. Patient characteristics and clinical outcomes are summarized in the table.[Table: see text]

Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study.

4514 Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P<0.0001); PFS2 rates at 24 and 36 mos are in the Table. The unadjusted OS HR for LEN + PEMBRO vs SUN (from the primary analysis [Motzer 2021, NEJM]) was 0.66 (95% CI 0.49–0.88); the HR for OS adjusted for subsequent therapy was 0.54 (bootstrap 95% CI 0.39–0.72). Conclusions: LEN + PEMBRO had a statistically significant and clinically meaningful benefit over SUN in the CLEAR study. These findings remained consistent after accounting for subsequent therapies, as evidenced by prolonged PFS2 and adjusted OS. Results further support LEN + PEMBRO as a standard of care in 1L aRCC. Clinical trial information: NCT02811861. [Table: see text]

PBRM1 genomic alterations as a predictive biomarker to immune checkpoint inhibitors (ICI) and/or anti-angiogenic therapies (anti-VEGF) in metastatic renal cell carcinoma (mRCC): A systematic review and meta-analysis.

e16515 Background: Combination therapy with ICI and anti-VEGF has become the standard first-line (1L) therapy for metastatic clear cell RCC (mccRCC). However, about 25% of patients (pts) are long responders to anti-VEGF monotherapy. PBRM1 genomic alterations (ga) are present in around 40% mccRCC pts and contradictory results have been reported about its role as a predictive biomarker. We performed a systemic review and meta-analysis to assess the role of PBRM1 ga as a predictive biomarker of response to ICI, anti-VEGF, or its combination. Methods: A systematic review of PubMed, EMBASE, Cochrane, and Web of Science databases was performed (February 2022) to identify studies involving mRCC pts who received systemic therapy and had PBRM1 status and clinical outcomes reported. Study design, baseline characteristics, treatment data, and hazard ratios (HRs) with 95% confidence intervals (CI) for each clinical outcome were extracted. HRs were combined across studies using a random effect model. The primary endpoint was to correlate PBRM1 status with progression-free survival (PFS) to anti-VEGF, ICI, or its combination. Results: The systematic review included 12 out of 892 publications (n = 6528 pts), 98% (n = 6372) mccRCC; 3297 pts (51%) treated with anti-VEGF monotherapy, 1574 (24%) ICI (PD-L1 (n = 1019, 65%) or CTLA4 + anti PD-L1 (n = 555, 35%)), 997 pts (15%) anti-VEGF + ICI, and 660 pts (10%) with other therapies (e.g., mTORi or INF). PBRM1 status was assessed by NGS in 3841 pts (59%) and detected in 1595 (41%). Nine out of 12 publications were considered for the meta-analysis; excluding those with duplicated pts or lack of information. Six studies (n = 2593 pts) evaluated PBRM1 status in first-line (1L) therapies, including anti-VEGF in monotherapy (n = 1487, 57%) and ICI (n = 1106, 43%; combined w/anti-VEGF (n = 773), w/CTL4 (n = 262) or in monotherapy (n = 71)). In 1L setting, PBRM1 ga pts had longer PFS under monotherapy with anti-VEGF ( PBRM1 ga 44%; HR = 0.74 (95% CI, 0.62 - 0.88), p < 0.01) but not under ICI ( PBRM1 ga = 42%; HR = 1 (95% CI, 0.85 - 1.17), p = 0.38) nor ICI + anti-VEGF treatment ( PBRM1 ga = 33.5%; HR = 0.93 (95% CI, 0.73 - 1.18), p = 0.56). Two studies evaluated PBRM1 status in second line (2L) ICI-treated mRCC pts (n = 517 pts). PBRM1 ga pts had longer PFS under ICI in 2L ( PBRM1 ga = 36%, HR = 0.64 (95% CI, 0.49 - 0.83), p = 0.0007). Conclusions: mRCC pts with PBRM1 ga showed longer PFS to 1L anti-VEGF and 2L ICI therapy, supporting its role as a predictive biomarker. Anti-VEGF + ICI combination de-escalation strategies merits further investigation in PBRM1 ga mRCC patients.

Comparison of immune checkpoint inhibitor monotherapy versus Sorafenib in unresectable hepatocellular carcinoma.

e16160 Background: Combination immune checkpoint inhibitors (ICI) or with a vascular endothelial growth factor receptor (VEGFR) agent is now the standard 1st line (1L) therapy in patients with advanced/unresectable hepatocellular carcinoma (uHCC). Currently, there is a paucity of data on the use of ICI monotherapy when combination ICI/VEGFR is contraindicated. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety outcomes of ICI monotherapy versus sorafenib in patients with uHCC in the 1L setting. Methods: A systematic search of electronic databases was conducted for randomized controlled trials comparing ICI versus sorafenib in the treatment of uHCC. Efficacy endpoints were overall survival (OS), objective response rates (ORR), and progression free survival (PFS). Safety endpoints of interests were any adverse events (AE) and > grade 3 AEs. We performed random effects meta-analysis to estimate odds ratio (OR) with 95% confidence intervals for individual endpoints. Results: A total of 2 studies with 1521 patients were included in the final analysis. Compared to sorafenib, ICIs were associated with improved OS [OR 0.75; 95% confidence interval (CI) 0.6-0.94]. Similarly, ICI had increased odds of ORR [OR 2.99; 95% CI 1.93-4.62] and PFS [OR 1.41; 95% CI 1.07-1.85] compared to the sorafenib arm. In the safety analyses, ICIs were associated with reduced risk of > grade 3 AE [OR 0.40; 95% CI 0.22-0.72] and any AEs [OR 0.25; 95% CI 0.12-0.55] when compared to sorafenib. Conclusions: Our meta-analysis suggests that ICI monotherapy has improved OS, PFS, ORR, and better safety profile in 1L uHCC compared to sorafenib.

Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).

8561 Background: MPM is an aggressive malignancy without curative treatment. ONCOS-102 is an oncolytic adenovirus expressing GM-CSF (Ad5/3-D24-GMCSF) with a clinically documented ability to stimulate local and systemic immune responses and re-modulate the tumor microenvironment, both as a monotherapy and in combination with anti-PD1 blockade. The study objectives included determining safety and tolerability, efficacy and immunological activation in repeat tumor biopsies, and correlations with clinical outcomes. Methods: Following a safety run-in of n = 6 pts, 25 patients were randomized to receive ONCOS-102 intratumorally under CT or US guidance at a dose of 3 x 1011 Virus Particles on Day 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22, or control comprising six cycles of P/C only. Both treatment-naïve (1L) and previously treated patients (2L) were enrolled. Imaging was done at baseline, Day 43-64 and 127-148 and tumor biopsy were collected at baseline and at Day 36. Final survival analysis (n = 25) was performed after 30 mo follow up. Multiplex immunofluorescence for immune cell subsets, RNASeq and qPCR was performed on repeat tumor samples. Results: The most frequent adverse events were anaemia, neutropenia and asthenia reported by > 50% in both groups with more frequent reports of pyrexia and nausea in the experimental (exp) group. No difference in the rate of severe events (Gr 3/4 acc to NCI CTCAE vs 4.0) were observed. 30-month survival rate (n = 25) was 34.3 % vs 18.2 % (NS) with mOS of 19.3 mo (95% CI: 4.6, NA) vs 18.3 mo (95% CI: 3.1, 28.9) in the exp group vs control. For patients treated in the 1L setting, 30 mo survival was 33.3 % in the exp group (n = 8) and 0% in the control group (n = 6) with mOS of 25.0 months and 13.5 months, respectively (NS). mPFS was unchanged from prior cut-offs; 9.8 months in the exp group and 7.6 in the control (NS). ONCOS-102 + P/C induced a pronounced increase in tumor infiltration by CD4+, CD8+ and granzyme B expressing CD8+ T-cells as well as M1:M2 macrophage polarization in patients with disease control (n = 13) vs progressing patients (n = 3). The data from RNAseq and qPCR analysis will be presented. Conclusions: The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted Clinical trial information: NCT02879669.

Outcomes of second-line therapies in patients with metastatic de novo small cell prostate cancer (SCPC) and treatment-emergent neuroendocrine prostate cancer (tNEPC).

e17022 Background: De novo SCPC and tNEPC in metastatic castrate resistant prostate cancer (mCRPC) are rare, aggressive cancers with a poor prognosis. After first-line (1L) platinum chemotherapy (PLT), there is no consensus on 2L treatments. This multi-institutional, retrospective study examines practice patterns among clinicians and evaluates the outcomes of patients (pts) with SCPC or tNEPC in the 2L setting. Methods: After IRB approval, pts with a pathologic diagnosis of SCPC or tNEPC (any % of SC or NE histology defined by institutional review) were identified. Pts diagnosed between 2000-2020 who received 1L PLT and any 2L systemic therapy (tx) for SCPC or tNEPC were included. Standardized data collection templates containing demographic, clinical, and pathologic variables were collected. The primary endpoint was objective response rate (ORR) to 2L tx. Secondary endpoints included PSA response, time on 2L treatment, and overall survival (OS) from time of 2L tx. Data was analyzed using descriptive statistics. Results: Forty-two pts (21 SCPC, 21 tNEPC) from 6 institutions were included. At SCPC/tNEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 60.5, 68.0) and median PSA of 3.0 ng/dL (IQR 0.5, 21.8). The most common sites of metastasis included lymph node (78.6%), bone (54.8%), and liver (52.4%). For 1L tx, 37 pts (88.1%) received PLT and 5 (11.9%) had PLT + immunotherapy (IMM). For treatment to the prostate, 21 (51.2%) had none, 7 (17.1%) radiation (RT), 9 (22.0%) surgery, 3 (7.3%) RT + surgery, and 1 (2.4%) brachytherapy alone. Concurrent ADT was given to 32 pts (76.2%) in the 1L and 2L. At last follow-up, 34 pts (81.0%) were dead, 4 (9.5%) were alive, and 4 (9.5%) were lost to follow-up/censored. For 2L tx, 10 pts (23.8%) received PLT, 8 (19.0%) taxane monotherapy (TAX), 10 (23.8%) IMM, 8 (19.0%) other chemotherapy (CHX), and 6 (14.3%) other tx. Among 38 pts evaluable for response, the ORR was 15.8% (6 pts with PR: 4 PLT, 1 IMM, 1 CHX). PSA response ≥ 50% to 2L tx was seen in 5 of 29 pts with PSA data (17.2%). Other outcomes data are reported in Table. Conclusions: In this retrospective study, pts with SCPC or tNEPC who reached 2L tx received a wide variety of treatment regimens, reflecting the lack of consensus in this tx setting. ORR was low and overall prognosis was poor in the 2L regardless of tx choice. Pts on 2L immunotherapy seemed to have the shortest mOS. [Table: see text]

Reasons for oncologist and urologist treatment choice in metastatic castration-sensitive prostate cancer (mCSPC): A physician survey linked to patient chart reviews in the United States.

5065 Background: Based on level 1 evidence of overall survival, ASCO/NCCN/AUA guidelines uniformly recommend novel hormonal therapy (NHT) or chemotherapy (CHT) added to androgen deprivation therapy (ADT) as standard of care in mCSPC. However, real-world evidence across US healthcare systems suggests most patients receive ADT +/- first generation non-steroidal antiandrogens (NSAA). Reasons behind the lack of treatment intensification (TI) in mCSPC have not been studied. Methods: Data from medical charts of patients initiating mCSPC treatment from Jul ’18-Nov ‘21 were retrospectively extracted from multiple US academic/community practices. Oncologists and urologists who treated these patients were surveyed to provide reasons for treatment choices including prostate specific antigen (PSA) goals and explicit reasons for not prescribing NHT. Descriptive statistics (Fishers exact tests) were used to compare outcomes between groups; p-values for odds ratios (OR) were generated via Wald test. Results: 65 oncologists and 42 urologists provided data on 621 patients. Median age at initial mCSPC treatment start was 68.0 years, 58% were White, 25% Black, 84% had de novo metastases, 30% had high-volume disease including 22% with visceral metastases, and 83% had ECOG PS score ≤1. In the first-line (1L) setting, most mCSPC patients received ADT±NSAA alone (69%), while TI rates with ADT+NHT (26%) or ADT+CHT (4%) were low. An additional 27% (n = 166/621) received subsequent TI while still castration-sensitive. According to the physician survey, the top 5 reasons why their patients did not receive initial NHT were perceptions about: drug tolerability (38%), lack of clinical trial evidence of overall survival improvement (31%), lack of reimbursement (26%), patient financial constraints (20%), and questions about sequencing NHTs earlier vs later in disease (21%). Regarding treatment goals for PSA response, physicians more frequently reported a relative (%) reduction than an absolute PSA reduction (85% vs 51%). Oncologists considered a median PSA reduction of 50% (IQR 25-75) adequate vs 75% (IQR 50-90) among urologists. Urologists had higher rates of TI at 1L and/or subsequent treatment in patients who were still castration-sensitive (p < 0.01). Physicians who aimed for deeper PSA reduction of 75-100% were more likely (OR = 1.63; p = 0.034) to provide TI in 1L compared with physicians with less aggressive PSA goals (0-49%). Conclusions: To our knowledge, this is the first study identifying reasons for underutilization of intensified treatment in mCSPC. While survey results suggest perceptions of tolerability and lack of efficacy and financial considerations affect NHT use, in practice, non-guideline driven PSA reduction goals are associated with low rates of TI. These results demonstrate the need for further medical education.

Real-world, population-based study of treatments, survival and healthcare use in advanced urothelial carcinoma of the bladder.

e16538 Background: Prior single institutional studies and case series suggest that management of urothelial carcinoma of the bladder (UCB) can be highly variable across different centers. To better contextualize emerging therapies and their place in management, we aimed to characterize current population-based treatment patterns, outcomes, and healthcare resource utilization. Methods: Using real-world registries and administrative data, we analyzed a contemporary cohort of patients diagnosed with advanced UCB from 2010 to 2017 in the large province of Alberta, Canada. The study time period was selected to allow for adequate follow-up. The Kaplan-Meier method was used to plot estimates of overall survival (OS) and Cox proportional hazards model was constructed to determine the associations of clinical characteristics with outcomes. Summary statistics were used to describe healthcare resource use. Results: We included 1,146 advanced UCB patients. Median age was 73 (IQR 65-81) years, majority (78%) were men, and most (69%) had a Charlson comorbidity index of 0 to 1. Only 363 (32%) were referred, consulted with oncologists, and received palliative systemic therapy. Common regimens consisted of platinum-based doublet in the first-line (1L) setting and single-agent chemotherapy or immunotherapy in the second-line (2L) setting. Only 116 (32%) of the 1L treated patients proceeded to 2L. Median OS was 9.8 months (10.2 and 5.3 months in treated and untreated patients, respectively). After adjusting for confounders, receipt of at least one line of systemic therapy was associated with improved OS (HR 0.79, 95% CI 0.65-0.95, P = 0.011) as was urban residence with more access to oncology care (HR 0.82, 95% CI 0.73-0.92, P = 0.001). Median number of emergency department visits was 4 (IQR 2-7) per patient. Median number of hospitalizations and duration of admissions were 3 (IQR 2-5) per patient and 10 (IQR 6-16) days, respectively. Conclusions: In our population-based sample, the poor prognosis of UCB may be largely attributed to the low receipt of systemic therapy rather than the burden of comorbidities or acute care encounters. Since treatment attrition is significant, efforts to streamline referral to and consultation with oncologists at the time of metastatic diagnosis may optimize the use of appropriate systemic therapies and improve survival. This is increasingly important as novel, more effective therapies for advanced UCB are introduced into the treatment armamentarium.

Impact of trilaciclib on multilineage chemotherapy-induced myelosuppression events in patients with extensive-stage small cell lung cancer: Post-hoc analyses of data from randomized clinical trials.

8568 Background: Trilaciclib is a short-acting CDK4/6 inhibitor administered prior to chemotherapy for multilineage myeloprotection. Reduced occurrence of chemotherapy-induced myelosuppression (CIM) events across neutrophil, red blood cell, and platelet lineages was reported in 3 Phase 2 clinical trials of trilaciclib versus placebo in patients with extensive-stage small cell lung cancer (ES-SCLC). In this post-hoc trial analysis, we further assessed the impact of trilaciclib on the occurrence of single and concurrent multilineage CIM events. Methods: Analyses were conducted separately by line of chemotherapy. In the first-line (1L) setting, pooled data from the G1T28-05 and G1T28-02 trials, in which trilaciclib or placebo was administered prior to etoposide, carboplatin, and atezolizumab [E/P/A] and E/P, respectively, were used. In the 2/3L setting, analyses were based on data from the G1T28-03 trial where patients received trilaciclib or placebo prior to topotecan. The proportion of patients with single and concurrent multilineage CIM events and incidence rate were estimated per cycle and during the first 4 cycles of chemotherapy. Severe (grade ≥ 3 per CTCAE definition) CIM events of neutropenia (SN), anemia (SA), and thrombocytopenia (ST) were assessed. Concurrent CIM events were defined as having 2 or 3 lineage-specific CIM events overlap for ≥ 1 day. As sensitivity analyses, the occurrence of CIM events in patients with ES-SCLC receiving 1L treatment in the G1T28-05 and G1T28-02 studies was analyzed separately. Results: Compared with placebo, fewer patients receiving trilaciclib had single-lineage CIM events and concurrent events in 2 or 3 lineages during cycles 1–4 of 1L chemotherapy using pooled data from G1T28-05 and G1T28-02 (Table). A similar trend was observed in the 2/3L setting. Generally, SN occurred more frequently in earlier cycles, whereas SA and ST tended to occur later. The sensitivity analysis in each individual 1L trial yielded consistent results with the pooled analysis. Conclusions: Patients with ES-SCLC receiving trilaciclib prior to chemotherapy had fewer single and concurrent multilineage CIM events than patients receiving placebo. Clinical trial information: NCT03041311, NCT02499770, NCT02514447. [Table: see text]

Progression and mortality post-immunotherapy discontinuation among patients with BRAFV600-mutant (BRAF+) metastatic melanoma.

9531 Background: Immunotherapy (IO) is commonly used to treat BRAF+ metastatic melanoma (MM) patients in the first line (1L) setting and has demonstrated durable outcomes in clinical trials. However, most patients discontinue IO therapy for toxicity, disease progression, or other reasons. To date, no multi-center or nationwide US-based study has examined treatment patterns and outcomes for patients with BRAF+ MM post discontinuation of 1L IO. The aim of this study is to describe real-world treatment patterns and outcomes among patients who discontinued 1L IO. Methods: This retrospective cohort study used the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) database, the harmonized customized data from Flatiron and ConcertAI. Patients were ≥18 years old, had a diagnosis of BRAF+ MM, were treated with pembrolizumab, nivolumab, or ipilimumab + nivolumab on or after 9/1/2014, and then discontinued 1L therapy. Reason for discontinuation was extracted from medical records. Descriptive statistics were used to describe baseline characteristics and treatment patterns. Kaplan–Meier curves were used to analyze time to progression or death (TTPD) and time to death (TTD). Results: Of the 898 included patients (mean age: 61 years; male: 65%); 46% initiated ipilimumab + nivolumab, 24% nivolumab, and 30% pembrolizumab. The most common reasons for 1L discontinuation were toxicity (26%) and progression (25%). Medical records noted 5.3% completed therapy on discontinuation and 34.5% provided no reason of discontinuation with median duration of therapy (MDOT) of 379 and 138 days respectively. At 6 months, 34 % (n = 303) remain on IL IO. MDOT for patients who discontinued IO due to toxicity and those who discontinued due to progression were 54 and 63.5 days respectively. Patients who discontinued due to toxicity had a median time of 142 days to next treatment. TTPD was best for patients who discontinued therapy due to completion or toxicity (6-month progression rate: 13% and 20%). Patients who discontinued due to progression did especially poorly (6-month progression rate: 59%). About 33% of patients (n = 296) needed second line (2L) therapy, and the majority (80.7%) received combination BRAF+ targeted therapy. Overall, 38% and 50% of patients died post IO discontinuation for any reason at 1 and 2 years, respectively. 31% of patients had brain metastases and a greater proportion (56%) died within a 2-year period compared with those without brain metastases (56% vs 49%, p = 0.0036). Conclusions: IO, although effective, is not curative for all patients. A significant number of patients discontinue therapy due to progression. Patients with BRAF+ MM who progress early on 1L IO therapy have a high risk of death and should be considered for other therapy options, including targeted therapy.

Trial in progress update on ENGOT-cx8/GOG-3024/innovaTV 205: Addition of a new cohort with first-line (1L) tisotumab vedotin (TV) + pembrolizumab (pembro) + carboplatin (carbo) ± bevacizumab (bev) in recurrent/metastatic cervical cancer (r/mCC).

TPS5603 Background: Despite the use of platinum-taxane doublets ± bev in eligible patients (pts), overall survival (OS) outcomes for pts with r/mCC remain poor. With the US approval of pembro + chemotherapy ± bev in the 1L setting for r/mCC with ≥1% of programmed death ligand 1–positive cells in the tumor, an unmet need remains for pts who do not meet this threshold and for pts who progress or are intolerant to standard treatment (tx). TV is a tissue factor–directed antibody–drug conjugate that has been granted accelerated approval in the United States for the tx of adults with r/mCC with disease progression on or after chemotherapy. To develop more effective treatments, we investigated TV in combination with agents with known activity in cervical cancer. We conducted a 2-part, multicohort phase 1b/2 trial, ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081), to evaluate TV in combination with bev, pembro, or carbo. The phase 1b dose-escalation phase of innovaTV 205 established the recommended phase 2 dose (RP2D) and the feasibility of these doublet combinations (Monk et al, IGCS 2021). Moreover, we recently reported encouraging antitumor activity from the dose-expansion cohort of TV + carbo (1L; confirmed objective response rate [ORR], 55%; median duration of response [DOR], 8.3 mo) and TV + pembro (second-line; confirmed ORR, 38%; median DOR, 13.8 mo) (Vergote et al, ESMO 2021). The current report describes the design of a new, ongoing dose expansion cohort in the innovaTV 205 study to evaluate the combinations of TV, pembro, and carbo ± bev. Methods: A new cohort has been added to the innovaTV 205 study, comprising adult pts with recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma of the cervix with no prior systemic therapy and an Eastern Cooperative Oncology Group score of 0 or 1. Pts will be treated with the RP2D of TV (2.0 mg/kg) + carbo (AUC 5 mg/mL), pembro (200 mg), and bev (15 mg/kg) every 3 weeks or with TV + carbo (AUC 5 mg/mL) and pembro (200 mg). To assess the regimen’s initial tolerability, there will be a dose-limiting toxicity evaluation period that will consist of completion of 1 tx cycle of 21 days for 6 pts enrolled to receive the quadruplet combination. The primary endpoint of this dose expansion phase is confirmed ORR per RECIST v1.1; secondary endpoints include DOR, time to response, progression-free survival, OS, and safety. Enrollment is ongoing in the United States and Europe, with additional sites planned globally. Clinical trial information: NCT03786081.

Efficacy and safety of low-dose radiotherapy (LDRT) concurrent atezolizumab plus chemotherapy as first-line therapy for ES-SCLC : Interim analysis of Phase II MATCH trial.

e20611 Background: The IMpower 133 trial represents the current SoC in the 1L setting for pts with ES-SCLC but still needs further efficacy improvement such as objective response rate (ORR, ̃60% in both arms) which may lead to survival benefit. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. We have reported that LDRT plus ICIs in pretreated ES-SCLC was well tolerated with an improved efficacy. Here we conducted MATCH study to investigate the clinical benefits of adding LDRT to Atezo plus chemotherapy in ES-SCLC pts as 1L therapy. Methods: The MATCH study was a single-arm phase II trial conducted in eight centers across China. A Simon’s minimax two-stage design was adopted. Pts with measurable disease per RECIST v1.1 at baseline with ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was ORR confirmed by investigators after two consecutive evaluations ≥ 4 weeks apart. The secondary endpoints included disease control rate (DCR) and safety. Results: This is the report on the completed 1st phase of the trial. By the cutoff date of 26th August 2021, of the first 21 evaluable pts, 20 were males; mean age was 60.2 y and 85.7% pts had ECOG PS of 1. Previous smokers were 85.7%. Most pts were staged T4 (n = 15, 71.4%), N3 (n = 18, 85,7%) and M1(n = 17, 81.0%). The most common sites of metastasis were bone (47.1%) and liver (11.8%). Median follow-up was 4.0 m (range: 2.6-8.0 m). The confirmed ORR was 95.2% (95% CI, 76.2%-99.9%), among whom all pts were PR. DCR was 100%. The safety profile was consistent with the previous reports. Neutrophil count decreased (66.7%), white blood cell count decreased (42.9%) and anaemia (38.1%) were the most common grade 3-4 adverse events. No grade 5 AE occurred. Two pts experienced AEs leading to treatment withdrawal. IrAEs by preferred term were reported in 3(14.3%) pts: 2 were immune-mediated hyperthyroidism (grade 2) and 1 was immune-mediated enterocolitis (grade 3). No radiation pneumonitis occurred. Conclusions: The study met the response criteria for 1st phase. The combination of LDRT and Atezo plus chemotherapy showed promising benefit and was tolerable in pts with ES-SCLC. The 2nd phase is ongoing. Clinical trial information: NCT04622228.

195P REACH AUT: Efficacy and safety of first-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) from a real-world (RW) study: 3rd interim analysis

In 1L setting, RIB is the only CDK4/6 inhibitor that showed a significant overall survival benefit across three phase 3 trials. REACH AUT — the only non-interventional trial on a CDK4/6 inhibitor in Austria to date, evaluated the RW clinical experience of RIB+ET (aromatase inhibitor [AI] or Fulvestrant [FUL]) in pre-, peri- or postmenopausal patients (pts) with HR+, HER2– MBC.

Management of Patients With Advanced Urothelial Carcinoma in an Evolving Treatment Landscape: A Qualitative Study of Provider Perspectives of First-Line Therapies.

The treatment landscape in locally advanced/unresectable or metastatic urothelial carcinoma (aUC) has evolved with the use of immune checkpoint inhibitors (ICIs) in the first line (1L) and platinum-refractory settings and with the recent approval of avelumab as 1L maintenance therapy for patients achieving disease control with platinum-containing regimens. Oncology provider perspectives and decision-making processes regarding aUC management, especially with the integration of recently approved strategies, such as maintenance therapy, have not been well-described. Qualitative interview study with US oncologists and oncology nurses in academic and community settings in August 2020. Interviews explored decision-making around aUC 1L treatment eligibility determinants and selection, programmed cell death 1 ligand 1 (PD-L1) testing practices, and use of maintenance therapy. Thematic analysis was used to identify drivers of 1L treatment decisions. Eighteen oncologists (women, 11%; >15 years in practice, 55%; academic, 39%) and 18 oncology nurses (women, 94%; >15 years in practice, 34%; academic, 50%) participated. Providers preferred platinum-based regimens in 1L setting and reserved 1L ICI monotherapy for frail patients. Providers preferred chemotherapy followed by switch maintenance ICI, as opposed to concurrent combination chemotherapy and ICI, followed by ICI as continuation maintenance. Decision-making was driven by need to adhere to treatment decision-making guidelines, characteristics of the patient, treatment efficacy and patient preference. Providers adhered to guidelines and level I evidence in decision-making in the aUC 1L setting. Future studies should further evaluate barriers to the adoption of standard-of-care strategies and factors impacting decision-making in the real-world setting.

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study.

PurposeThe LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.Patients and MethodsPostmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.ResultsA total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).ConclusionsThe fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03772353.

Clinical evidence and insights supporting the use of avelumab first-line maintenance treatment in patients with advanced urothelial carcinoma in the Asia-Pacific region.

Until recently, international and Asia‐specific guidelines for advanced urothelial carcinoma (UC) recommended first‐line (1L) platinum‐based chemotherapy, followed by second‐line (2L) anti‐PD‐1 or anti‐PD‐L1 immune checkpoint inhibitor (ICI) therapy where possible, or 1L ICI therapy in cisplatin‐ineligible patients with PD‐L1+ tumors. However, long‐term outcomes remain poor and only a minority of patients receive 2L therapy. The JAVELIN Bladder 100 trial—which assessed avelumab (anti‐PD‐L1 antibody) as 1L maintenance therapy plus best supportive care (BSC) versus BSC alone in patients with advanced UC that had not progressed with 1L platinum‐based chemotherapy—is the only phase 3 trial of ICI‐based treatment in the 1L setting to show significantly improved overall survival, and this treatment approach is now recommended in updated treatment guidelines. Available data from the trial suggest that efficacy and safety in patients enrolled in the Asia‐Pacific region were similar to findings in the overall population. In this review, we discuss the treatment of advanced UC, with a specific focus on studies in the Asia‐Pacific region, and summarize key findings supporting the use of avelumab 1L maintenance as a standard of care in this setting both in cisplatin‐eligible and cisplatin‐ineligible patients and irrespective of PD‐L1 status.