Line Platinum-based Chemotherapy Research Articles

Surufatinib plus PD-1/L1 inhibitors as maintenance therapy following first line (1L) platinum-based chemotherapy combined with PD-1/L1 inhibitors in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC).

e15109 Background: Pts with ES-SCLC have a poor prognosis. PD-1/L1 inhibitors combined with chemotherapy as 1L treatment has been demonstrated to improve the survival. Yet, pts are prone to progression after chemo-immunotherapy followed by anti-PD-1/L1 monotherapy. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) combined with PD-1/L1 inhibitors in pts with ES-SCLC as 1L maintenance therapy. Methods: Key inclusion criteria were cytologically or pathologically confirmed ES-SCLC, ECOG PS 0-1, no disease progression after 4-6 cycles platinum-based chemotherapy combined with PD-1/L1 inhibitors. Enrolled pts received surufatinib (250mg, po, QD) plus PD-1/L1 inhibitors (same as that in prior 1L therapy: Durvalumab, Sintilimab, Toripalimab or Serplulimab) until disease progression or intolerable toxicity. The primary endpoint is progression free survival (PFS) per RECIST 1.1 by investigator. Results: From Sept 2022 to July 2023, 21 pts were enrolled. The median age was 62 years. 90.5% were male, 85.7% were former and current smokers and 52.4% had ECOG PS of 0, 11 pts completed 6 cycles of platinum-based chemotherapy combined with PD-1/L1 inhibitors, and 12 pts received durvalumab in 1L therapy. As of 20 Nov, 2023, the median follow-up duration was 9.2 months. Objective response rate (ORR) was 14.3% and DCR (disease control rate) was 71.4%. The mPFS of 1L maintenance therapy was 4.0 months (95%CI: 2.0-5.6). The mPFS from 1L treatment to disease progression was 8.7 months. mOS was not reached, with 3 mo- , 6 mo- and 9 mo- OS rate was 100%, 94.4% and 75.6%, respectively. 21 (100%) pts experienced treatment-emergent adverse events (TEAEs), and 8 (38.1%) pts experienced grade ≥3 TEAEs, most commonly with platelet count decreased, neutrophil count decreased and pneumonia. There was no treatment-related death. Conclusions: Surufatinib combined with PD-1/L1 inhibitors showed encouraging efficacy and tolerable safety profile as 1L maintenance therapy. Further OS follow-up is warranted. Clinical trial information: NCT05509699 .

Sintilimab plus anlotinib as second or further-line therapy for extensive disease small cell lung cancer: a phase 2 investigator-initiated non-randomized controlled trial

Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200mg on day one and oral daily anlotinib 12mg on days 1-14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Forty-two patients were enrolled between August 29, 2019 and December 26, 2021at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9-28.2). The median PFS was 6.1 months (95% CI: 5.0-7.3). The OS was 12.7 months (95% CI: 7.1-18.2). The ORR was 56.8% (21/37, 95% CI: 40.0-73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7-99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.

Abstract B013: Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC)

Abstract Background: Advanced and recurrent EC remains a therapeutic challenge with rising mortality rates and few options beyond first line platinum-based chemotherapy and immunotherapy. Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and maytansinoid payload DM4, is FDA-approved for patients with FRa-high platinum resistant ovarian cancer (PROC). FRa is also expressed in EC and is associated with poor prognosis. Here, we evaluate FRa expression levels and associations with other molecular alterations, including in HER2, MYC and CCNE1, in patients with advanced/recurrent serous EC. Methods: Paraffin fixed tumor tissue from 110 patients who signed prescreening consent for a phase 2 study testing the combination of MIRV with pembrolizumab in recurrent/persistent serous EC (NCT03835819) were analyzed for FRα expression by IHC (Ventana, Inc). All patients had advanced or recurrent MSS serous EC and had received 1-3 prior lines of therapy. FRα positivity was defined as ≥50% of cells with ≥2+ membrane staining based on results from a phase 1b study of mirv and pembrolizumab in PROC (Matulonis U, SGO 2018 abstract 74). HER2/neu expression was assessed by independent pathology review at the treating institution. Tumor mutational burden (TMB), amplification of CCNE1, MYC and ERBB2 and other somatic mutations were determined in tumors with next generation sequencing (NGS). Results: 37 of 110 tumors were determined to be FRa positive (FRa+) with FRa ≥50% for an overall positivity rate of 33.63%. The median membrane positivity was 20.5% (IQR: 3-51.25). Within a cohort of 44 patients with available tumor NGS, the average TMB was 6.23 (SD: 3.34) and did not differ between FRα+ and -negative (FRα-) tumors at 5.74 and 6.45, respectively (p=0.73). Of 32 tumors with HER2 IHC performed, 5 (16%) were both FRα+ and HER2+ (2+ or 3+); 7 (22%) were FRα+ and HER2-, 5 (16%) were FRα- and HER2+, and 15 (47%) had negative expression for both. CCNE1, MYC and ERBB2 amplifications were present in 1 (9%), 0 and 3 (27%) of FRα+ tumors, and 6 (23%), (8) 31%, and 2 (8%) and of FRα- tumors, respectively. There was no association between expression of FRα and HER2 (Fisher exact test, p=0.44), nor with amplification of CCNE1 (p=0.65), MYC (p=0.08) and ERBB2 (p=0.14). The most common co-occurring somatic mutations were in PIK3CA, with similar frequency in FRα+ (55%) and FRα- (42%) tumors. Conclusions: An FRα positivity rate of 33.6% in this large cohort of serous EC tumors supports further clinical development of MIRV in this high-risk subtype of EC. Within a limited cohort subset, it does not appear that FRα expression correlates with TMB or HER2 expression, or with CCNE1, MYC or ERBB2 amplifications. This data highlights the importance of comprehensive testing of EC tumors for all relevant biomarkers that may guide selection of targeted therapies. Additional studies are needed to explore FRα expression in other molecular subsets of EC and to determine the longitudinal stability of ADC target expression. Citation Format: Rebecca L. Porter, Sandy Elias, Niya Xiong, Madeline Polak, Kayla Fahey, Nabihah Tayob, Courtney Qi, Carina Feeney, Swati Narayan, Jennifer Curtis, Susana Campos, Carolyn Krasner, Elizabeth Lee, Elizabeth Stover, Alexi A. Wright, Joyce F. Liu, Ursula A. Matulonis, Panagiotis Konstantinopoulos. Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B013.

Early recurrence, time-to-recurrence, and recurrence patterns: Assessing their impact on survival outcomes in head and neck squamous cell carcinoma (R/M-HNSCC) patients treated with first line platinum-based chemotherapy.

R/M-HNSCC patients typically receive 1L platinum-based chemotherapy with pembrolizumab or cetuximab. However, the outcomes for patients with early recurrence (<6 months) remain unclear due to their exclusion from most 1L studies. This study aimed to assess the impact of time-to-recurrence intervals (TTRI) and recurrence patterns on the survival of R/M-HNSCC patients. We identified non-curable R/M-HNSCC patients at our institution from 1/2008 through 6/2020. We analyzed the outcomes of early recurrent patients who received 1L systemic treatment, with different TTRIs and recurrence patterns. Our study included 234 eligible patients. The majority (47%) experienced early recurrence (<6 months), while 22%, 20%, and 11% had recurrences at 6-12 months, >12 months, and de novo metastasis, respectively. The platinum-based regimen was the most commonly used chemotherapy (86%), with cetuximab and immunotherapy utilized in 3% and 5% of cases, respectively. Significant differences in PFS and OS were observed among TTRI groups. For patients with early recurrence, both platinum-doublet and monotherapy treatments significantly improved OS. Locoregional recurrence (47%) was the most common, followed by distant metastasis (22%) and both (20%). Recurrence patterns were significantly associated with OS but not with PFS. In multivariate analysis, TTRI ≥12 months significantly correlated with improved PFS (HR 0.51; p = 0.004) and OS (HR 0.58; p = 0.009), whereas recurrent pattern did not. TTRI significantly influenced the survival, while recurrence patterns did not. In our study, the retrospective design limited our ability to definitively establish whether early recurrent R/M-HNSCC patients would benefit more from platinum-doublet. Despite poor prognosis, early recurrent patients benefited from 1L systemic treatments. Given the variation in prognoses, TTRI should be considered a stratification factor in future clinical trials.

Optimising utility of selective internal radiation therapy in metastatic pancreatic adenocarcinoma.

622 Background: Selective internal radiation therapy (SIRT) using Yttrium-90 containing microspheres has established benefit for a number of cancers but there is limited data available on the utility of SIRT for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: In this retrospective audit we identified 32 patients who received SIRT using Yttrium-90 microspheres for metastatic PDAC in 2 treatment centres. All patients received SIRT in combination with chemotherapy. Data was analysed from electronic medical records. Results: Thirty two patients with metastatic PDAC who had SIRT were identified. Patients received SIRT (median activity 1.6 GBq) in combination with chemotherapy (platinum-based; n = 23, non-platinum-based; n = 9). Three patients remain alive and 29 patients were included in the survival analysis. For the entire group, the median OS was 15 months (range 4-49), median survival from time of SIRT was 9 months (range 1-48) and median PFS from time of SIRT was 4 months (range 1-25). Median PFS (6 vs 2 months, p=0.0011) and OS (13 vs 4 months, p=0.0004) from SIRT was significantly better when SIRT was given with 1st-line therapy vs with 2nd-line and beyond. Median PFS from SIRT was significantly better (10 vs 2 months, p=0.0020) when combined with 1st line platinum-based chemotherapy (n=14) vs non-platinum based treatment (n=6). 18 month survival was 40% (n=13) with 9/13 patients having had SIRT with 1st line with platinum-based therapy. 24 month survival was 22% (n=7) with 7/7 patients having had SIRT with 1st line with platinum-based therapy. SIRT was well-tolerated with no associated 30-day all-cause mortality. Grade 3 adverse events were liver abscess (7%, n = 2), gastritis (7%, n = 2) and duodenitis (7%, n=2). Conclusions: This is the first report to analyse optimum utility of SIRT with chemotherapy in metastatic PDAC. Our data suggest SIRT in combination with 1st-line platinum agents contribute to the best outcomes in the setting and warrants further study.

Penpulimab combined with anlotinib in patients with R/M HNSCC after failure of platinum-based chemotherapy: a single-arm, multicenter, phase Ⅱ study

Treatment regimens for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after failure of platinum-based chemotherapy have been illustrated with limited efficacy. Here, we report a single-arm, multicenter, phase Ⅱ study of R/M HNSCC patients treated with a programmed cell death-1 antibody penpulimab (200 mg) and anlotinib (12 mg) after failing at least one line of platinum-based chemotherapy. Of 38 patients in total, 13 (34.21%) patients achieved partial response and 16 (42.11%) patients achieved stable disease. After a median follow-up of 7.06 months (range: 4.14-15.70 months),the independent review committee-assessed objective response rate was 34.21%, the disease control rate was 76.32%. The median progression-free survival was 8.35 months (95% confidence interval 5.95-13.11 months). Twelve patients died and the median overall survival (OS) was not reached. The 12-month OS rate was 59.76%. Grade 3/4 treatment-related adverse events occurred in 47.37% of the patients. Penpulimab combined with anlotinib demonstrated promising efficacy and manageable safety in R/M HNSCC patients after failure of platinum-based chemotherapy.

Overall Survival Following First and Second Relapse of DLBCL Treated with Therapies Including Autologous Transplant and CAR-T Cells: Results from the Lion Prospective Observational Registry

Background: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma (NHL) and is curable with first-line conventional chemotherapy, but a significant fraction of patients relapse or do not respond to initial therapy. There are a variety of treatments available for relapsed/refractory (RR) disease, including platinum-based salvage chemotherapy often used historically both with or without autologous stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy emerging more recently as a second-line option. We report survival data following 2 nd and 3 rd line therapy for RR DLBCL in a large contemporary prospective cohort. Methods: We selected patients (pts) from the Lymphoma Innovations ORIEN Network (LION) with diffuse large B-cell lymphoma, not otherwise specified and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (“double-hit” lymphoma) who had previously received R-CHOP chemotherapy. All patients had signed written consent. Clinical data were abstracted from medical records using standardized protocol. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2 nd (OS2) or 3 rd (OS3) line treatment until death, censoring patients alive at last follow-up. Comparisons of OS were performed using the log-rank test. Results: A total of 328 patients with RR DLBCL who received 2 nd line treatment were included, 177 of whom went on to receive 3 rd line therapy. Baseline characteristics included male sex in 205 pts (65%), stage III/IV disease in 244 pts (81%), and extranodal involvement in 183 pts (63%). Second line treatments included platinum-based salvage chemotherapy both with (99 pts) and without (88 pts) autologous stem cell transplant, rituximab plus gemcitabine and oxaliplatin (30 pts, grouped distinctly from platinum-based salvage chemotherapy), CAR-T therapy (43 pts), polatuzumab vedotin (17 pts), and other classes of treatment (51 pts). Median OS2 for 2 nd line platinum-based salvage chemotherapy with autologous transplant was 110.4 months compared with 50.4 months for platinum-based salvage chemotherapy without transplant. OS2 for platinum-based salvage chemotherapy with autologous transplant was 96.5% (95% CI 90-99) at 12 months, 90.7% (95% CI 81-96) at 24 months, and 79.3% (95% CI 67-88) at 60 months compared with 77.1% (95% CI 66-85) at 12 months, 65.5% (95% CI 52-76) at 24 months, and 38.1% (95% CI 21-55) for platinum-based salvage without transplant. OS2 for rituximab plus gemcitabine and oxaliplatin was 81.7% (95% CI 58-93) at 12 months, still 81.7% (95% CI 58-93) at 24 months, and 70.1% (95% CI 37-88) at 60 months. OS2 for CAR-T cell therapy was 75% (95% CI 50-89) at 12 months and 62.5% (95% CI 36-80) at 24 months, it could not be calculated at 60 months. OS2 for polatuzumab vedotin was 73.5% (95% CI 36-91) at 12 months and could not be calculated at 24 or 60 months. OS3 for platinum-based salvage chemotherapy with autologous transplant was 100% at 12 months and 83.3% (95% CI 27-98) at 24 months compared with 70.7% (95% CI 34-90) at both 12 and 24 months for platinum-based salvage without transplant. OS3 for rituximab plus gemcitabine and oxaliplatin was 75% (95% CI 13-96) at 12 months and 50% (95% CI 6-85). OS3 for CAR-T therapy was 86.3% (95% CI 75-93) at 12 months, 65.8% (95% CI 50-78) and 46.3% (95% CI 22-68) at 60 months. OS3 for polatuzumab vedotin was 53.4% (95% CI 24-76) at 12 months and 40.1% (95% CI 12-67) at 24 months. Conclusions: We observed a statistically significant difference by log-rank in OS2 in patients receiving platinum-based salvage chemotherapy followed by autologous stem cell transplant compared to other therapies in a contemporary cohort of pts with RR DLBCL. This difference is likely driven in part by transplant being a surrogate marker for efficacy of salvage chemotherapy. OS3 was also highest at 12, 24, and 60 months in patients receiving platinum-based salvage chemotherapy followed by transplant. Other therapies including CAR-T cells, polatuzumab vedotin, and rituximab plus gemcitabine and oxaliplatin did not demonstrate significantly different rates of overall survival in the 2 nd or 3 rd line setting.

CTNI-64. EFFICACY AND SAFETY OF ERDAFITINIB IN PATIENTS WITH HIGH-GRADE AND LOW-GRADE GLIOMAS AND PRESPECIFIED FIBROBLAST GROWTH FACTOR RECEPTOR ALTERATIONS (FGFRALT) IN THE RAGNAR TRIAL

Abstract BACKGROUND Erda is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat adults with locally advanced/metastatic urothelial carcinoma with susceptible FGFR3/2alt who have progressed during/after ≥1 line of platinum-based chemotherapy. RAGNAR interim results demonstrated tumor-agnostic efficacy in adults/adolescents with previously-treated advanced solid tumors with prespecified FGFRalt. Here we report results for patients with HGG/LGG. METHODS Patients with HGG/LGG harboring prespecified FGFR1-4alt (mutations/fusions), disease progression after ≥1 line of systemic therapy, and who exhausted standard therapies received oral erda until disease progression or intolerable toxicity. Primary endpoint: ORR by independent review committee (IRC). Secondary endpoints: DOR, disease control rate (DCR), investigator-assessed efficacy, and safety. Response was based on RANO criteria. RESULTS At data cutoff, 37 HGG (n = 30)/LGG (n = 7) patients received erda. In HGG (glioblastoma, n = 25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n = 24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). ORR in HGG was 10% by IRC (95%CI, 2-27) and 20% by Investigator (95%CI, 8-39); mDOR was not reached (m-F/U, 18.0mo); DCR was 57% (95%CI, 37-75). In LGG (m-age 22y; range 12-32), 4 (57%) had FGFR1 mutation (all FGFR1-K656E); 3 (43%) had FGFR fusion. ORR in LGG was 29% by IRC (95%CI, 4-71) and 14% by Investigator (95%CI, 0-58); mDOR was not reached; DCR was 71% (95%CI, 29-96). 17 HGG patients (57%) had TERT co-alterations; 9 (30%) had PTEN deletions. No HGG/LGG patients had IDH1/2 mutations. Most common (≥40%) adverse events (AEs): hyperphosphatemia, diarrhea, dry skin, dry mouth. 43% had serious AEs (treatment-related, 16%). 19% discontinued due to AEs. No treatment-related deaths occurred. CONCLUSIONS Erda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.

Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P= 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P= 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.

e17509 Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.

LATIFY: Phase 3 study of ceralasertib + durvalumab vs docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer that progressed on or after anti-PD-(L)1 and platinum-based therapy.

TPS9161 Background: Following progression on first- or second-line immunotherapy ± platinum-based chemotherapy (CT), the prognosis for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) is poor with limited alternative options to docetaxel. Ceralasertib is a selective inhibitor of Ataxia Telangiectasia and Rad3-related (ATR) protein kinase, which is activated in response to DNA damage. Clinical data suggest that ceralasertib may sensitize tumors to immunotherapy by biasing T cells to an immune-effective phenotype. Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that binds programmed cell death ligand-1 (PD-L1) and inhibits PD-L1-mediated suppression of T-cell activation. Combining ceralasertib with durvalumab may amplify the antitumor immune response, and potentially lead to durable tumor control. In the ongoing phase 2 HUDSON study in pts with locally advanced or metastatic NSCLC who progressed on anti-PD-(L)1 therapy and platinum-doublet regimen, ceralasertib + durvalumab showed promising efficacy with median progression-free survival (PFS) of 6.0 mos (80% CI, 4.6–7.5) and median overall survival (OS) of 15.9 mos (80% CI, 14.1–20.3). Methods: LATIFY is a phase 3, open-label, randomized, multicenter study in pts with NSCLC (NCT05450692). Key inclusion criteria are age ≥18 years; ECOG performance status 0–1; documented EGFR and ALK wild-type, and tumor cell PD-L1 status; and adequate organ and bone marrow function. Stable brain metastases are allowed. Pts should be eligible for second- or third-line therapy, and must have received an anti-PD-(L)1 therapy and a platinum-containing doublet regimen for locally advanced or metastatic NSCLC either separately or in combination, but no other prior therapies. Key exclusion criteria include mixed small-cell lung and NSCLC histology, unresolved toxicities of Grade ≥2 (NCI CTCAE v5.0) from prior therapy, active or prior autoimmune or inflammatory disorders, &gt; 1 line of prior anti-PD-(L)1 therapy (alone or in combination), and &gt; 1 line of platinum-based CT in a metastatic setting. Pts are randomized 1:1 to receive either oral ceralasertib 240 mg twice daily on Days (D) 1–7 with IV durvalumab 1500 mg on D8 (28-day cycle) or IV docetaxel 75 mg/m2 (D1, 21-day cycle). The primary objective is to assess efficacy by OS. Secondary objectives include evaluating efficacy by PFS, objective response rate and disease control rate by RECIST v1.1; duration of, and time to, response; time to second progression or death; OS at 12 mos; time to deterioration of health-related quality of life and physical function; determining the pharmacokinetics of ceralasertib; and assessing safety. Approximately 580 pts will be recruited from around 21 countries in the Americas, Europe, and Asia Pacific. Clinical trial information: NCT05450692 .

GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

TPS5622 Background: Elevated folate receptor-alpha (FRα) expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing a rational target for antibody drug conjugate (ADC) development in ovarian cancer. Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has received accelerated approval for patients with FRα positive platinum resistant ovarian cancer. MIRV in combination with BEV has demonstrated clinically meaningful activity, along with acceptable tolerability, in patients with FRα expressing ovarian cancer.1 Methods: GLORIOSA is a randomized, open-label, phase 3 study designed to evaluate the efficacy of in combination with bevacizumab compared with bevacizumab alone as maintenance for patients with FRα-positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers who have not progressed after second line platinum-based chemotherapy plus bevacizumab (which may be given on protocol for patients with high FRα tumor expression). Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1 CDx Assay (high expression; ≥ 75% of viable tumor cells staining at 2+ intensity) and 1 prior line of therapy is required for inclusion. GLORIOSA is designed to randomize 418 patients, 1:1 receiving intravenous MIRV at a dose of 6 mg/kg adjusted ideal body weight plus bevacizumab 15mg/kg every 3 weeks or receiving bevacizumab 15mg/kg every 3 weeks until disease progression or unacceptable toxicity. Radiological assessments will be conducted every 9 weeks (± 2 weeks) for 72 weeks, and subsequently every 18 weeks (± 3 weeks) until progressive disease (PD), death, the start of new anticancer therapy, or withdrawal of consent from the study (whichever occurs first). The primary efficacy endpoint is progression-free survival by investigator and will also be assessed as a sensitivity analysis. The secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. GLORIOSA is a global study that opened for enrollment in December 2022. Reference: 1. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023; 170: 241–247 Clinical trial information: NCT05445778 .

To Bev or Not to Bev during Ovarian Cancer Maintenance Therapy?

Maintenance therapy with PARP inhibitors and bevacizumab is approved for ovarian cancer treatment in the first and second line settings, but selecting the optimal sequence is challenging due to restrictions on using the same medication twice. This review aims to establish guidelines for ovarian cancer maintenance therapy based on the strength of scientific evidence, the most effective treatment strategy, and the impact on the healthcare system. Six questions were formulated to evaluate the scientific evidence supporting different maintenance therapy options using the AGREE II guideline evaluation tool. The questions address the acceptability of reusing the same medication, the efficacy of bevacizumab and PARP inhibitors in the first and second line settings, the comparative efficacy of these medications, the potential benefit of combination maintenance therapy, and the economic impact of maintenance therapy. Based on the available evidence, bevacizumab should be preserved for second line maintenance therapy, and maintenance therapy with PARP inhibitors should be offered to all advanced ovarian cancer patients who have responded to first line platinum-based chemotherapy. Additional molecular predictors for bevacizumab efficacy are needed. The presented guidelines offer an evidence-based framework for selecting the most effective maintenance therapy for ovarian cancer patients. Further research is necessary to refine these recommendations and improve outcomes for patients with this disease.

Efficacy of avelumab in the treatment of oncourological malignances. Results of registration studies and own experience

Background. In the JAVELIN Bladder 100 trial, 1st line maintenance with avelumab in combination with best supportive care significantly increased (9.2 months) overall survival compared to best supportive care in patients with locally advanced or metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy: 29.7 months versus 20.5 months, respectively. Trial results led to inclusion of avelumab into the international guidelines as a standard of care with the highest level of evidence. Combined therapy with avelumab + axitinib in patients with previously untreated metastatic renal cell carcinoma showed higher progression-free survival and objective response rate compared to sunitinib in all IMDC (International Metastatic Renal Cancer Database Consortium) groups. Avelumab + axitinib is one of the immuno-oncology combinations with proven effectiveness for progression-free survival and objective response rate.Aim. To evaluate the effectiveness of avelumab in treatment of oncological urological diseases in routine clinical practice. Materials and methods. At the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology - branch of the National Medical Research Radiology Center, 12 patients with locally advanced inoperable and metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy in combination with gemcitabine received maintenance avelumab therapy. Median follow-up was 10 months. Primary endpoints were overall survival from the start of avelumab maintenance therapy and safety.Combined therapy with avelumab + axitinib was administered in 18 patients with metastatic renal cell carcinoma. Median follow-up was 9 (3-16) months. Overall survival, progression-free survival, response rate and safety in the overall population and according to IMDC groups were evaluated.Results. At data cut-off (March 2023) with median follow-up of 10 months, overall survival was 100 %, progression-free survival was 66.7 % (among patients who received more than 3 infusions - 100 %). Progression-free survival was higher in patients with tumors of the lower urinary tract compared to upper (72.5 % versus 60 %), complete response to induction platinum-based chemotherapy compared to partial response and stable disease (100 % versus 66.7 %) and presence of metastases in the lymph nodes only compared to visceral and bone metastases (100 % versus 66.7 %). Adverse events were observed in 4 (66.7 %) patients.Among 18 patients who received avelumab + axitinib, complete response was observed in 2 (11.1 %) patients, partial response in 6 (33.3 %) patients, stable disease in 9 (50 %) patients, disease progression in 1 (5.6 %) patient. Response to therapy was observed in patients of all prognosis groups; for large (&gt;5 cm) metastases in the lungs, soft tissues, lymph nodes and bones response was observed 3 months after treatment start. Overall survival for this follow-up duration was 100 %, progression-free survival was 96.4 ± 11.2 %. Adverse events were observed in 8 (44.4 %) patients, and in 6 (75 %) of them they were grade I—II and did not require infusion regimen correction or axitinib dose reduction.Conclusion. Avelumab maintenance therapy in the 1st line is the standard of care for patients with locally advanced and metastatic urothelial cancer without disease progression during 1st line platinum-based chemotherapy. Maintenance therapy allows to achieve better overall survival and progression-free survival irrespective of the choice of platinum regimen (cisplatin or carboplatin), response to platinum-based chemotherapy, number of chemotherapy cycles, tumor localization and advancement.Experience of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology confirms results of the JAVELIN Bladder 100 trial on the effectiveness of avelumab maintenance therapy in routine clinical practice. Combination drug therapy with avelumab and axitinib in patients with metastatic renal cell carcinoma is an effective and safe treatment method which allows to achieve fast objective response and has good tolerability in patients irrespective of IMDC group or metastasis location. Effectiveness and favorable safety profile of avelumab + axitinib combination were proven in the context of routine clinical practice.

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat

BackgroundSmall cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.MethodsElevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.ResultsMYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.ConclusionsMYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

Abstract CT066: HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor

Abstract Background: Standard therapies for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) that has progressed after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs) offer only limited benefit. Human epidermal growth factor receptor 3 (HER3) is often expressed in primary NSCLC tumors, and HER3 expression is commonly observed in patients with EGFR mutations. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3-DXd demonstrated efficacy and safety in a phase 1 study in patients with EGFRm NSCLC that progressed following an EGFR TKI and platinum-based chemotherapy (PBC) (U31402-A-U102; NCT03260491). In previously reported results from dose-escalation/expansion, HER3-DXd 5.6 mg/kg demonstrated a manageable safety profile and promising efficacy (confirmed objective response rate by blinded independent central review [BICR] of 39%, median duration of response of 7.0 months, and median progression-free survival of 8.2 months) in a subset of patients (n=44) with advanced EGFRm NSCLC that progressed after ≥1 line of PBC and a third-generation EGFR TKI. Trial Design: HERTHENA-Lung02 (NCT05338970) is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of HER3-DXd vs PBC in patients (≈560) with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have received 1 or 2 lines of EGFR TKI treatment including a third-generation EGFR TKI and had disease progression following treatment with a third-generation EGFR TKI. Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no). The primary endpoint is progression-free survival by BICR (per RECIST v1.1). The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America. Citation Format: Balazs Halmos, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, Tony Mok. HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT066.

Audit of Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma Treated in the Early Access Scheme

Purpose: Maintenance avelumab following first line platinum-based chemotherapy prolongs survival in advanced urothelial carcinoma. We audited the outcomes and tolerability of maintenance avelumab in patients who have been started on treatment in the EAMS setting.

High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors: A TYME network study

BackgroundWe reported the efficacy and safety results of high-dose, continuous-infusion Ifosfamide,in patients with advanced thymoma (TM) and thymic carcinoma (TC). MethodsThis was a multicentric, prospective study in patients with advanced TM or TC, who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis or anti-PD(L)1 was allowed.Patients received Ifosfamide (1 g/m2/day) and sodium-2-mercaptoethanesulfonate (1 g/m2/day), as continuous infusion, via a portable pumps for 14 consecutive days.Treatment was administered every 4 weeks until progression or unacceptable toxicity, up to a maximum of 6 cycles.The primary endpoint was the overall response rate (ORR) assessed by RECIST1.1.Secondary endpoints included disease control rate (DCR), Progression-free survival (PFS), overall survival (OS), and safety. ResultsEighteen patients were enrolled from October 2020 to January 2022.Twelve patients had a TC, 5 a TM and 1 a mixed TM/TC. Sixty-one percent of patients (11/18) had stage IVB disease according to Masaoka-Koga, and 39% (7/18) had an ECOG-PS 2. The median number of previous lines of therapy was 2 (range:1–5), and 72% (13/18) and 61% (11/18) of patients were pretreated with an anti-angiogenesis drug and an anti-PD(L)1 drug respectively.The ORR and the disease control rate (DCR) were 28 % (95 %CI: 10 %-53 %) and 67 % (95 %CI: 41 %-86 %), respectively.The median follow-up for PFS was 17.3 months (95 %CI: 4.3-NA), and median PFS was 5.4 months (95 %CI: 2.9–6.4). The median duration of response and SD was respectively 19.6 months (95 %CI: 3.5-NA) and 6.0 months (95 % CI: 3.8–6.4).In patients with TC, the ORR and DCR were 15 % (95 % CI: 2 %-45 %) and 54 % (95 % CI: 25 %-81 %), respectively. In the subgroup of 5 patients with TM, 2 PR and 3 SD were observed.Most patients had only mild (grade 1–2) AEs, the most common being nausea and vomiting (39%; 7/18) and transaminases elevation (33%; 6/18).Twenty-two percent of patients (4/18) experienced an AEs of grade 3 and required ifosfamide dose reduction. No patients had severe AEs. ConclusionHigh-dose continuous-infusion Ifosfamide can be considered as a valuable treatment option in patients with advanced thymic epithelial tumors.

Response to first line platinum-based chemotherapy in mismatch repair deficient (MMRd)/ microsatellite instability high (MSI-high) endometrial carcinoma

BackgroundAround 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity in MMRd/MSI-H EC, especially response to first-line platinum-based treatment. Patients and methodsWe performed a multicentric retrospective analysis reporting the response to first line platinum CT in MMRd/MSI-H EC patients. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) with first line platinum-based CT. ResultsA total of 112 patients MMRd/MSI-H EC from 8 centers were identified. Median overall survival was 58.0 months (95% CI: 45.3–95.1). Among them, 78 patients received first line platinum CT in recurrent/metastatic setting. With a median follow up of 32.6 months (min: 0.03; max: 135.0), ORR and DCR (disease control rate) were 50% (95% CI: 38.5–61.5) and 68% (95% CI: 56.4–78.1), respectively. Median PFS and OS from first line platinum-based CT was 7.8 months (95% CI: 6.0–9.0) and 51.9 months (95% CI: 28.0-NE), respectively. Median PFS with ICI in second line (n = 48) was 10.7 months (95% CI: 3.4-NE) from ICI initiation. ConclusionORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.

1022P A phase II study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed first line treatment

KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. In the phase II study, promising anti-tumor activity was seen with KN046 in subjects with non-small cell lung cancer (NSCLC). Here, we reported the efficacy and safety results of KN046 in second line treatment of advanced NSCLC from Cohort A and B in this study. This is an open-label, multi-center, multiple cohorts, single arm study to evaluate the efficacy, safety and tolerability of KN046 in NSCLC. Subjects with NSCLC who had failed from first line platinum-based doublet chemotherapy without PD-(L)1 immune checkpoint blockade were enrolled. Subjects with EGFR mutation and/or ALK translocation will be excluded. All subjects enrolled will receive KN046 3 mg/kg (Cohort A) and 5 mg/kg (Cohort B) Q2W IV administration, respectively. Primary endpoint was objective response rate (ORR) per RECIST version 1.1 by BICR. Between May 16, 2019 and April 30, 2020, 64 subjects with metastatic NSCLC who failed first line treatment were enrolled. At the data cutoff of August 31, 2021, the median follow-up was 21.6 months (95% CI, 20.3, 23.2). Among all 64 subjects, the ORR was 14.1% (9/64, 95% CI, 6.64, 25.02%), median progression-free survival (mPFS) was 3.7 months (95% CI, 2.9, 5.5) and median overall survival (mOS) was 18.4 months (95% CI, 12.9, 21.9). Furthermore, the ORR was 17.1% (7/41, 95% CI, 7.15, 32.06%), mPFS was 3.7 months (95% CI, 2.76, 5.45) and mOS was 19.8 months (95% CI, 13.04, 23.36) in non-squamous NSCLC (n=41). And in squamous NSCLC (n=20), the ORR was 10.0% (2/20, 95% CI, 1.23, 31.70%), mPFS was 7.4 months (95% CI, 1.81, 14.39) and mOS was 12.9months (95% CI, 8.97, -). 27(42.2%) out of the 64 subjects had experienced treatment-related adverse event (TRAE) at grade 3 or higher levels. The most common TRAEs of grade 3 or higher were infusion reaction (7/64 [10.9%]), hepatic dysfunction (3/64 [4.7%]), pneumonia (2/64 [3.1%]), etc. The bispecific antibody, KN046 was well tolerated and effective as second line treatment of advanced NSCLC. KN046 showed promising OS benefit in both squamous and non-squamous NSCLC.