Chemotherapy-free Interval Research Articles

EP.13B.12 Chemotherapy Sensitivity for Recurrent Small-Cell Lung Cancer Based on Chemotherapy-Free Interval and Treatment Regimens

EP.13B.12 Chemotherapy Sensitivity for Recurrent Small-Cell Lung Cancer Based on Chemotherapy-Free Interval and Treatment Regimens

Efficacy and safety of PARP inhibitor maintenance therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials.

The landscape of poly (ADP-ribose) polymerase (PARP) inhibitor treatment for ovarian cancer (OC) is continually evolving. This research aimed to evaluate the efficacy and safety of PARP inhibitors compared to placebo as a maintenance therapy for OC patients. We conducted a search of PubMed, Embase, Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs) involving the use of PARP inhibitors as maintenance therapy in OC patients, up to 16 June 2024. Data regarding progression-free survival (PFS), overall survival (OS), chemotherapy-free interval (CFI), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and treatment-emergent adverse events (TEAEs) were aggregated. Pooled hazard ratio (HR) and their corresponding 95% confidence intervals (CI) were calculated for PFS, OS, CFI, TFST, and TSST. Additionally, the relative risk (RR) and 95% CI for TEAEs were determined. This meta-analysis encompassed 20 RCTs involving 7,832 participants. The overall analysis demonstrated that maintenance therapy with PARP inhibitors led to significant improvements in PFS (HR: 0.398, 95% CI = 0.339-0.467, 95% PI = 0.219-0.724), OS (HR: 0.677, 95% CI = 0.582-0.788, 95% PI = 0.546-0.839), CFI (HR: 0.417, 95% CI = 0.368-0.472, 95% PI = 0.265-0.627), TFST (HR: 0.441, 95% CI = 0.391-0.498, 95% PI = 0.308-0.632), and TSST (HR: 0.574, 95% CI = 0.507-0.649, 95% PI = 0.488-0.674) compared with placebo. Subgroup analyses further indicated that PARP inhibitor maintenance treatment significantly improved PFS, regardless of homologous recombination status (all p < 0.05). However, the risks of any grade (RR = 1.046, 95% CI = 1.032-1.059, 95% PI = 1.028-1.055) and grade ≥3 TEAEs (RR = 2.931, 95% CI = 2.641-3.253, 95% PI = 2.128-3.792) were increased by PARP inhibitor maintenance therapy compared to placebo. Our research elucidated the benefits of maintenance therapy with PARP inhibitors in patients with OC, showing improvements in PFS, OS, CFI, TFST, and TSST. Vigilance regarding TEAEs is paramount for clinicians implementing PARP inhibitor maintenance therapy in clinical practice. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024560286.

Phase 2 dose-ranging study to evaluate the efficacy and safety of liposomal irinotecan (LY01610) as a second-line treatment for patients with relapsed small cell lung cancer

This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60mg/m2, 80mg/m2, and 100mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60mg/m2, 80mg/m2, and 100mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval <90 days. In all 66 patients, the ORR was 32% (21/66, 95% confidence interval [CI], 21-44), with a median DoR of 5.2 months (95% CI, 3.0-8.3). Median PFS and OS were 4.0 (95% CI, 2.9-5.5) and 9.7 (95% CI, 7.2-12.3) months, respectively. The ORR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 33% (10/30), and 30% (9/30), respectively. The median DoR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 4.2 (95% CI, 2.8-not reached), 6.9 (95% CI, 2.5-9.9), and 4.0 (95% CI, 2.7-6.8) months, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) in the 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 47% (14/30), and 50% (15/30), respectively. Themost common≥grade 3 TRAEs of all 66 patients were neutropenia (27%), leukopenia (24%) and anemia (15%). LY01610 exhibited promising clinical efficacy and manageable safety profiles in patients with relapsed SCLC, the 80mg/m2 dose group had the best benefit-risk ratio. This study was supported by Luye Pharma Group Ltd.

Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in patients (Pts) with relapsed small cell lung cancer (SCLC): Results from a phase 2 expansion cohort.

8094 Background: LUR has been approved in the US and elsewhere for treatment of adult pts with metastatic SCLC and disease progression on or after platinum-based chemotherapy. Preclinical studies found synergy for LUR with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The phase 1b part defined the recommended dose at LUR 2.0 mg/m2 on Day (D)1 + IRI 75 mg/m2 on D1,D8 every three weeks with primary G-CSF prophylaxis, and found promising results for the combination in SCLC pts after first-line therapy (Ponce Aix S. Ann Oncol 2019; 30: Abst 471P). Methods: Eligibility criteria for this cohort of the phase 2 part of this study included: confirmed SCLC, progression after one platinum-containing regimen, controlled brain metastases and ECOG PS ≤ 1. The primary endpoint was overall response rate (ORR). Results: 101 evaluable pts were enrolled. Baseline characteristics included: median age 63 (range, 45-77 y), 60.4% males, 76.2% ECOG PS 1, 28.7% CNS involvement, 39.6% bulky disease and 41.6% pretreated with immunotherapy. Chemotherapy-free interval (CTFI) was &lt;90 d in 51.4% of pts (26.7% had CTFI&lt;30 d. Median CTFI was 85 d (range, 0-323 d). Median number of cycles per pt was 6 (range, 1-34); 25.7% received &gt;10 cycles. Efficacy results by independent review committee are summarized in the table. Treatment-related adverse events (AEs) were observed in 99.0% of pts (grade ≥3 in 69.3%). Most relevant grade ≥3 events/abnormalities were neutropenia (52.5%), anemia (27.7%), diarrhea (19.8%), fatigue (18.8%), and febrile neutropenia (9.9%). Treatment-related SAEs occurred in 25.0% of pts and 5.0% discontinued due to treatment-related AEs. No treatment-related deaths occurred. Conclusions: The LUR/IRI combination showed promising antitumor activity and a manageable safety profile in these pts with poor prognosis, particularly those with CTFI&gt;30 d. These encouraging results reinforce the rationale for including this combination as an experimental arm in the ongoing pivotal phase 3 LAGOON trial (NCT05153239) in relapsed SCLC with CTFI&gt;30 d. Clinical trial information: NCT02611024 . [Table: see text]

IDeate-Lung02: A phase 3, randomized, open-label study of ifinatamab deruxtecan (I-DXd) vs treatment of physician’s choice (TPC) in relapsed small cell lung cancer (SCLC).

TPS8126 Background: SCLC is an aggressive malignancy, and patients (pts) with extensive stage (ES)-SCLC have a relatively short median overall survival (OS), with limited treatment options beyond first-line (1L) therapy. B7 homolog 3 (B7-H3 [CD276]) is a transmembrane protein expressed in many solid tumors but with low/no expression in normal tissue. In SCLC, B7-H3 is highly expressed and associated with poor prognosis and lack of response to standard therapy. I-DXd is a B7-H3-directed antibody–drug conjugate comprising an anti-B7-H3 mAb linked to a topoisomerase I inhibitor payload (DXd) via a stable cleavable linker, designed to enhance selective tumor cell death and reduce systemic exposure. I-DXd demonstrated durable efficacy (objective response rate [ORR] 52.4%; median duration of response [DoR] 5.9 mo; median OS 12.2 mo) irrespective of B7-H3 status, with a manageable safety profile in 21 ES-SCLC pts with a median of 2 prior lines of therapy in a Phase 1/2 trial (NCT04145622). I-DXd is being investigated in an ongoing Phase 2 trial in pretreated ES-SCLC, IDeate-Lung01 (NCT05280470). We describe a Phase 3 trial comparing the efficacy and safety of I-DXd vs TPC in relapsed SCLC. Methods: IDeate-Lung02 (NCT06203210) is a global, multicenter, randomized, open-label, Phase 3 trial in adult pts with relapsed SCLC who have received 1 prior line of platinum-based therapy and have an ECOG PS of ≤1; pts with asymptomatic brain metastases are eligible. Pts are randomized 1:1 to receive I-DXd 12 mg/kg iv every 3 wks (n = 234) or TPC (n = 234; topotecan, amrubicin, or lurbinectedin). Randomization is stratified by chemotherapy-free interval after 1L therapy (&lt; 90 vs ≥90 days); TPC (topotecan vs amrubicin vs lurbinectedin); prior treatment with PD-(L)1 (yes vs no); and presence/history of asymptomatic brain metastases (yes vs no). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 wks for 48 wks, then every 12 wks. Dual primary efficacy endpoints are ORR per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary efficacy endpoints are ORR per investigator; progression-free survival, DoR, disease control rate and time to response by BICR and investigator; and patient-reported outcomes. Safety endpoints include incidence of treatment-emergent adverse events (TEAEs), deaths, serious TEAEs, and TEAEs leading to dose modification or discontinuation. Immunogenicity of I-DXd and relationship between B7-H3 expression and clinical outcome are also secondary objectives. ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and OS will be analyzed using a log-rank test at a 2-sided 4% significance level, under a 2-look group sequential design. Clinical trial information: NCT06203210 .

Cyclophosphamide maintenance to extend combination chemotherapy-free interval in metastatic pancreatic ductal adenocarcinoma.

Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50mg/day), were included in the analysis. 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Correlation between histopathological response by neoadjuvant DCF therapy and the clinical efficacy of palliative platinum-containing regimens for recurrent ESCC.

272 Background: Docetaxel and cisplatin, 5-FU (DCF) therapy has established as the standard neoadjuvant treatment for resectable locally advanced esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. If patients showed recurrence of ESCC after neoadjuvant DCF therapy, platinum-containing regimens were used as palliative treatment in the clinical practice. However, there were no data of correlation between histopathological response by neoadjuvant DCF therapy and clinical efficacy of palliative platinum-containing regimens for recurrent ESCC. Methods: We retrospectively reviewed patients with ESCC who received neoadjuvant DCF therapy and R0 resection between Feb 2014 to June 2022 in our hospital. We evaluated histopathological response by neoadjuvant DCF therapy based on the Japanese Classification of Esophageal Cancer 12th (Grade 0: ineffective, Grade 1: slightly effective, Grade 2: moderately effective, Grade 3: markedly effective [pT0]) and objective response rate (ORR), progression-free survival (PFS) during platinum-containing regimens as clinical efficacy outcomes. We analyzed the correlation between histopathological response and ORR, PFS using Fisher’s exact tests and the log-rank tests. In addition, we analyzed clinical factors related to clinical efficacy of palliative chemotherapy using Cox proportional hazards models. Results: In this study, 398 patients received neoadjuvant DCF therapy and we identified 88 eligible patients with recurrence. Among 88 patients, 33 patients initially received palliative chemotherapy and analyzed. Patients’ characteristics were followed; Male/Female: 26 (78.8%)/7 (21.2%), median age (range): 64 (46-76) years, PS 0/1/2: 1 2(36.4%)/17 (51.5%), 4 (12.1%). Histopathological response 0/1/2/3 were in 1 (3.0%)/23 (69.7%)/7 (21.2%)/2 (6.1%) patients, respectively. Among these 33 patients, 23 patients received platinum-containing regimens. In the patients who received palliative chemotherapy, the ORR were 34.8% (8/23) in histopathological response 0/1 group and 44.4% (4/9) in histopathological response 2/3 group, with no statistical difference (p = 0.696). The median PFS was 2.43 (95%CI: 2.33-2.53) months in histopathological response 0/1 group and 4.04 (95%CI: 0-10.77) months in histopathological 2/3 group (HR[95%CI]: 1.121 [0.413-3.043]). Multivariate analysis using Cox proportional hazards models revealed chemotherapy-free-interval (CFI) &lt; 6 months (HR[95%CI]: 3.594 [1.027–12.580]) was independent prognostic factor, whereas histopathological response didn’t show the significance (HR[95%CI]: 0.723 [0.195–2.678]). Conclusions: Histopathological response by neoadjuvant DCF therapy did not affect the efficacy of platinum-containing regimens for recurrent ESCC, while CFI might be the prognostic factors.

Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥30 days and without central nervous metastases

ObjectivesThis report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645–654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland. Materials and methodsPatients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients). ResultsLurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan. ConclusionWith the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan.

Treating patients with platinum-sensitive extensive-stage small-cell lung cancer in a real-world setting.

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive disease with poor 5-year survival. The first-line standard-of-care for ES-SCLC is platinum plus etoposide, along with 1 of the immune checkpoint inhibitors atezolizumab or durvalumab. Although SCLC first-line therapy often leads to rapid responses, treatment becomes more challenging at progression, particularly for those with a chemotherapy-free interval (CTFI) of ≤6 months. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for SCLC no longer specify treatment recommendations in this setting, but options approved by the US Food and Drug Administration include topotecan and lurbinectedin. Participation in a clinical trial is recommended as an option regardless of CTFI. Other NCCN-recommended regimens are paclitaxel, irinotecan, temozolomide, and cyclophosphamide/doxorubicin/vincristine, among others. Nivolumab and pembrolizumab are options in those not previously treated with a checkpoint inhibitor. For patients with platinum-sensitive SCLC (CTFI >6 months), preferred treatment per the NCCN Guidelines® for SCLC is retreatment with platinum and etoposide, although the use of immune checkpoint inhibitors is discouraged if there is progression on a drug in this class. Further research on immunotherapies and combination regimens is ongoing, and continuing work on the subcharacterization of SCLC may lead to better precision of therapies that promote more durable responses in individual patients with ES-SCLC.

Clinical benefits of pulmonary resection for lung metastases from pancreatic cancer.

Systemic chemotherapy is generally used for metastatic pancreatic cancer; however, pulmonary resection may be a treatment option for lung oligometastases from pancreatic cancer. The current study aimed to clarify the oncological outcomes and clinical benefits of pulmonary resection for lung metastases. Of 510 patients who underwent pancreatic resection for pancreatic cancer, 44 patients with recurrence of isolated lung metastases and one patient with simultaneous lung metastases were evaluated. Of the 45 patients, 20 patients were selected as candidates for pulmonary resection based on clinical factors such as recurrence-free interval (RFI) from pancreatectomy to lung metastases, number of lung metastases, and serum CA19-9 level. The post-recurrent survival of patients with pulmonary resection was significantly better than that of patients without pulmonary resection. Fourteen of the 20 patients with pulmonary resection developed tumor recurrence with a median disease-free survival (DFS) of 15 months. Univariate analyses revealed that an RFI from pancreatectomy to lung metastases of ≥28 months was associated with better DFS after pulmonary resection. Of the 14 patients with an RFI of ≥28 months, pulmonary resection resulted in prolonged chemotherapy-free interval in 12 patients. Furthermore, repeat pulmonary resection for recurrent tumors after pulmonary resection led to further cancer-free interval in some cases. Although many patients had tumor recurrence after pulmonary resection, pulmonary resection for lung metastases from pancreatic cancer may provide prolonged cancer-free interval without the need for chemotherapy. Pulmonary resection should be performed for the patients with a long RFI from pancreatectomy to lung metastases.

Adverse Effect of the Duration of Antibiotic Use Prior to Immune Checkpoint Inhibitors on the Overall Survival of Patients with Recurrent Gynecologic Malignancies.

Antibiotic use preceding immune checkpoint inhibitor (ICI) treatment has been associated with a decreased efficacy of ICI in solid tumors. In this study, we evaluated the effect of antibiotic use before ICI therapy on oncological outcomes. We examined patients with recurrent gynecologic malignancies at two academic institutions. The clinical data, including antibiotic use within 60 days of ICI initiation, type of antibiotics, reasons for antibiotic use, body mass index, tumor site, chemotherapy-free interval, prior history of radiotherapy, disease control rate (DCR), and overall survival (OS), were assessed. Of 215 patients, 22.9% (n = 47) received antibiotics before ICI treatment. The most common cancer was ovarian (52.1%, n = 112), followed by cervical (24.7%, n = 53) and endometrial (16.7%, n = 36). When we divided the cohort based on antibiotic use before ICIs, there were no significant differences in the DCR and baseline characteristics between the two groups. On multivariate analyses, the variables associated with poor OS were previous use of antibiotics for a cumulative duration of >14 days (HR 2.286, 95% CI 1.210-4.318; p = 0.011); Eastern Cooperative Oncology Group 2 or 3 (HR 4.677, 95% CI 2.497-8.762; p < 0.001); and chemotherapy-free interval of <6 months (HR 2.007, 95% CI 1.055-3.819; p = 0.034). Prior use of antibiotics for a cumulative duration of >14 days was associated with reduced survival in recurrent gynecologic malignancies.

Real-World Outcomes With Lurbinectedin in Second-Line Setting and Beyond for Extensive Stage Small Cell Lung Cancer

BackgroundLurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients. MethodsA retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. ResultsLurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported. ConclusionThis real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.

Comparative Effectiveness of Lurbinectedin for the Treatment of Relapsed Small Cell Lung Cancer in the Post-Platinum Setting: A Real-World Canadian Synthetic Control Arm Analysis.

Based on findings from a single-arm, phase 2 basket trial (NCT02454972), lurbinectedin may be an effective treatment for individuals with small cell lung cancer (SCLC) who progressed on or after platinum-based chemotherapy. To estimate the comparative effectiveness of lurbinectedin versus the historical standard of care for relapsed SCLC in Canada. A synthetic control arm (SCA) analysis was conducted using real-world data. Population-level data were obtained from real-world databases in Alberta, Canada. Individuals diagnosed with SCLC who initiated post-platinum systemic therapy and met approximated eligibility criteria from the lurbinectedin trial were included in the SCA. Median overall survival (OS) in the SCA was estimated after adjusting for chemotherapy-free interval (CTFI; < 90 versus ≥ 90 days) and stage at initial diagnosis (extensive versus limited). The CTFI-adjusted hazard ratio was estimated using a Cox proportional hazards model. One hundred seventy-four individuals were included in the SCA and 105 in the lurbinectedin trial. The adjusted median OS in the SCA was 6.1 months (95% CI 5.4-7.7 months; unadjusted: 6.7 months, 95% CI 6.0-7.7 months) versus 9.3 months (95% CI 6.3-11.8 months) in the lurbinectedin trial. The adjusted hazard ratio comparing lurbinectedin with the historical standard of care (referent group) was 0.61 (95% CI 0.45-0.82; unadjusted HR: 0.72; 95% CI 0.54-0.97). The hazard ratio was more pronounced among individuals with CTFI ≥ 90 days (HR: 0.49, 95% CI 0.33-0.73). These findings suggest improved OS with lurbinectedin monotherapy versus the historical standard of care in Alberta, Canada.

Chemoradiotherapy plus hyperthermia (CRTH) versus chemoradiotherapy (CRT) alone in neoadjuvant treatment of soft tissue sarcoma: tumor response, treatment toxicity and disease control

Introduction Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. Materials and methods A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called ‘whoops procedure’, (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. Results All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). Conclusions Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.

A model-based head-to-head comparison of single-agent lurbinectedin in the pivotal ATLANTIS Study.

Lurbinectedin is a selective inhibitor of oncogenic transcription U.S. Food and Drug Administration (FDA)-approved for patients with relapsed small cell lung cancer (SCLC) as monotherapy at 3.2 mg/m2 every 3 weeks (q3wk). ATLANTIS was a phase 3 study in SCLC with lurbinectedin 2.0 mg/m2 plus doxorubicin 40 mg/m2 q3wk vs physician's choice, with overall survival (OS) as the primary endpoint and objective response rate (ORR) as the secondary endpoint. This work aimed to dissect the contribution of lurbinectedin and doxorubicin to antitumor effects in SCLC, and to predict the efficacy of single-agent lurbinectedin at 3.2 mg/m2 in ATLANTIS to allow for a head-to-head comparison with the control arm. The dataset included exposure and efficacy data from 387 patients with relapsed SCLC (ATLANTIS, n=288; study B-005, n=99). Patients in the ATLANTIS control arm (n=289) were used for comparison. Unbound plasma lurbinectedin area under the concentration-time curve (AUCu) and total plasma doxorubicin area under the concentration-time curve (AUCDOX) were used as exposure metrics. Univariate and multivariate analyses were conducted to determine the best predictors and predictive model for OS and ORR. OS baseline hazard was best described by a log-logistic distribution, with chemotherapy-free interval (CTFI), lactate dehydrogenase, albumin, brain metastases, neutrophils/lymphocytes ratio, AUCu, and the interaction between AUCu and AUCDOX as predictors. Effect of AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on CTFI. Head-to-head comparisons with predicted 3.2 mg/m2 lurbinectedin resulted in a positive outcome in ATLANTIS, with hazard ratio (95% prediction intervals [95% PI]) for OS of 0.54 (0.41, 0.72), and odds ratio (95% PI) for ORR of 0.35 (0.25, 0.5). These results support the superiority of lurbinectedin monotherapy for relapsed SCLC over other approved therapies.

A phase III study of lurbinectedin alone or in combination with irinotecan vs investigator's choice (topotecan or irinotecan) in patients with relapsed small cell lung cancer (SCLC; LAGOON trial).

TPS8613 Background: Lurbinectedin is a novel synthetic chemical entity that acts as an inhibitor of oncogenic transcription and is active in tumors addicted to transcription. A phase II Basket trial (NCT02454972) in patients with small cell lung cancer (SCLC) treated with lurbinectedin in the second-line setting showed overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months, with durable responses (43.0% ≥ 6 months). Based on these results, lurbinectedin was granted accelerated approval by the US FDA. An ongoing phase I/II trial (NCT02611024) is evaluating the lurbinectedin/irinotecan combination. Preliminary results showed ORR of 62% and median DoR of 5.7 months (2020 World Conference on Lung Cancer) warranting expansion to 100 patients. These results have supported the conduction of a phase III trial (LAGOON - NCT05153239). Methods: LAGOON is a randomized phase III clinical trial evaluating two experimental arms (lurbinectedin alone, 3.2 mg/m2 D1 q3wk, or lurbinectedin 2 mg/m2 D1 plus irinotecan D1, D8 q3wk) versus Investigator’s Choice (topotecan D1-5 q3wk or irinotecan D1 q3wk according to label) as control arm in relapsed SCLC patients. Approximately 705 patients will be enrolled. Central randomization will be implemented (1:1:1 ratio). Stratification will be done according to chemotherapy-free interval (CTFI) after first line (sensitive vs. resistant); prior anti-PD-(L)1; baseline central nervous system (CNS) involvement; lactate dehydrogenase value, and Investigator’s preference for the Control Arm. Main inclusion criteria include age ≥ 18 years, confirmed SCLC diagnosis, one prior line of platinum-containing chemotherapy with/without anti-PD-(L)1, and CTFI ≥ 30 days. Patients with CNS metastases can participate if pretreated and radiologically stable for at least 4 weeks. Main exclusion criteria include platinum-naïve patients, patients pretreated with more than one prior chemotherapy regimen (including platinum re-challenge), and prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors. An Independent Data Monitoring Committee will oversee the conduct of the study. An Independent Review Committee will provide the patient’s response at each tumor assessment endpoint to determine the best patient’s response and the date of objective response or progression/censoring according to RECIST v.1.1. Clinical trial information: NCT05153239 .

Efficacy and safety of lurbinectedin in elderly patients with relapsed SCLC.

8591 Background: Relapsed SCLC is a difficult-to-treat disease. A considerable number of SCLC patients are elderly with associated fragility and numerous comorbidities. Accelerated approval from the US FDA of lurbinectedin (Zepzelca) 3.2 mg/m2 q3wk as second-line therapy in metastatic small cell lung cancer (SCLC) was based on results from a phase 2 basket trial (NCT02454972) showing overall response rate of 35.2% and duration of response of 5.3 months. The ATLANTIS trial (NCT02566993) assessed the combination of lurbinectedin 2mg/m2/ doxorubicin (DOX) 40 mg/m2 as second-line treatment for SCLC vs. a control arm of topotecan/CAV. Methods: This post hoc analysis explores the efficacy and safety of lurbinectedin in relapsed SCLC patients ≥65 years included in both phase 2 basket (26 patients treated with lurbinectedin) and ATLANTIS (121 patients treated with lurbinectedin/DOX and 118 patients treated in the control arm) trials. This analysis did not include patients from the phase 2 basket trial with chemotherapy-free interval (CTFI) &lt; 30 days, as these patients were excluded in the ATLANTIS trial. Results: Median age was similar (72.5 in lurbinectedin basket vs. 69 in ATLANTIS lurbinectedin/DOX vs. 69 in ATLANTIS control arm), most were males (65.4% vs. 57.9% vs. 60.2%), with ECOG PS 1 (65.4% vs. 68.6% vs. 68.6%) and CNS involvement (7.7% vs. 10.7% vs. 15.3%). Median CTFI (days) was also similar (105.5 vs. 123 vs. 120). Median number of cycles was 4 vs. 6 vs. 4. Main efficacy and safety results are shown in the table. Treatment-related adverse events (AEs) were reported in 92.3%, 92.6% and 94.1% of patients, respectively (grade ≥3 in 50.0%, 59.5% and 81.4%). Conclusions: In elderly patients, lurbinectedin seems to be superior to the standard of care in terms of both efficacy (higher response rate and longer duration of response and overall survival) and safety (less associated hematological AEs), which reinforces its role as a treatment option in relapsed SCLC patients ≥65 years. Clinical trial information: NCT02454972 , NCT02566993 . [Table: see text]

IFCT-2105 lurbiclin real-world effectiveness and treatment sequences in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) who received lurbinectedin as part of the French Early Access Program (EAP-ATU).

8584 Background: Novel options are needed for pts with ES-SCLC after the failure of first-line chemotherapy. Lurbinectedin demonstrated efficacy in a landmark phase II study [Trigo et al. Lancet Oncol. 2020 May;21(5):645], and was granted EAP-ATU in France in June 2020. Methods: Multicenter, retrospective cohort of consecutive pts with histologically or cytologically confirmed ES-SCLC, who received at least one dose of treatment with lurbinectedin as part of the French EAP-ATU from June 2020 until March 2021, and gave consent for the data collection, were enrolled in 47 sites. Primary and secondary endpoints were description of clinical characteristics, and exposure to treatment, response, PFS, OS, safety. Results: 312 pts – 64% male, median age 65 years, 72% PS0-1, 47% with brain metastasis, 58% with previous immunotherapy – were enrolled. Lurbinectedin was administered as second-line in 44% of pts; 58% were chemotherapy-refractory. Pts received a median number of 3 cycles of lurbinectedin. Concurrent radiotherapy on metastases was delivered to 38% of pts. Lurbinectedin was discontinued because of progression/death/toxicity/other reasons in 83%/8%/5%/4% of pts. Grade3/4 events were observed in 9%/5% of pts. Response rate was 22% [95%CI 17-27%], disease control rate was 38% [95%CI 32-44%]. After a median follow-up of 20.8 months, median PFS and OS were 1.9 [95%CI 1.8-2] and 4.7 [95%CI 4-5.4] months; 6-month PFS and OS were 7% [4-10%] and 42% [95%CI 37-48%]. PS≤2 and chemotherapy-free interval≥90days were associated with significantly longer OS (HR = 0.71 [95%CI 0.53-0.95] and HR = 0.58 [95% CI 0.44-076] respectively). Main sites of progression were the lung (39% of pts), the brain (39% of pts), the liver (30% of pts), and the mediastinum (30% of pts). Subsequent treatment was administered to 154 pts after discontinuation of lurbinectedin, mostly consisting of topotecan (26% of pts); response/disease control rates, and median PFS of first subsequent treatment were 11% [95%CI 6-17%], 35% [95%CI 27-44%], and 1.9 [95%CI 1.7-2.3] months. Conclusions: Lurbinectedin provides an additional option from second-line for ES-SCLC, with efficacy outcomes comparable to that of historical treatments.

Hyperthermic intraperitoneal chemotherapy in platinum-sensitive relapsed epithelial ovarian cancer: The CHIPOR randomized phase III trial.

5510 Background: Standard treatment for patients with first platinum-sensitive relapse of epithelial ovarian cancer (EOC) is based on surgery and second-line systemic chemotherapy (CT). The role of hyperthermic intra-peritoneal chemotherapy (HIPEC) remains uncertain. Methods: The CHIPOR multicentric randomized phase III trial (NCT01376752), conducted in 31 institutions, enrolled patients with a first platinum-sensitive relapse (platinum-free interval of ≥6 months) of EOC. Patients were treated with 6 cycles of platinum and taxane based CT ± bevacizumab, and those amenable to a complete cytoreductive surgery at the end of CT were enrolled and randomly assigned to receive HIPEC (cisplatin 75 mg/m² at 41°C for 60 min) or not. Randomization was performed during complete cytoreductive surgery, stratified by center, surgical outcome (no residual disease vs residual &lt;0.25 cm), chemotherapy-free interval before relapse, and PARP inhibitor use (yes vs no). The primary endpoint was overall survival (OS). The target sample size was 404 evaluable patients, providing 80% power at 5% alpha after 268 deaths. Secondary endpoints included progression-free survival (PFS), peritoneal PFS, patient-reported outcomes, safety, and postoperative morbidity and mortality (≤60 days after surgery). Results: Between May 11, 2011, and May 14, 2021, 415 patients were randomized. Baseline characteristics were balanced between treatment arms. At the data cutoff (Jan 8, 2023), with a median follow-up of 6.2 years, 268 patients (65%) had died. Efficacy results are summarized below. Conclusions: HIPEC significantly improves OS and peritoneal PFS of women with first platinum-sensitive relapse of EOC treated with second-line platinum-based CT followed by secondary complete cytoreductive surgery. Ongoing analyses, including patient reported outcome, BRCA status, bevacizumab exposure, and subsequent therapy, will be presented. Clinical trial information: NCT01376752 . [Table: see text]