Prior Platinum Research Articles

Impact of gastrectomy on efficacy and safety of second‐line chemotherapy patients with advanced gastric cancer: Exploratory analysis of two randomized phase III trials

AbstractAimsSecond‐line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Although many patients receiving SLC have undergone gastrectomy, the impact of gastrectomy on SLC remains unclear.Patients and MethodsThe objective was to evaluate the impact of gastrectomy on SLC for AGC. A total of 290 eligible patients registered in two randomized phase III trials evaluating SLC for patients with AGC was classified into the prior gastrectomy group (PGG; n = 187) or the no gastrectomy group (NGG; n = 103). We compared overall survival (OS), progression‐free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety between these two groups. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW).ResultsThe PGG had better performance status (p = 0.001), more prior platinum agent (p < 0.001), and more frequent peritoneal metastasis (p = 0.006) than the NGG. The PGG had significantly better OS (13.8 vs. 9.3 mo; hazard ratio [HR]: 0.59; p < 0.001) and PFS (4.7 vs. 2.8 mo; HR: 0.58; p < 0.001) than the NGG. The PGG had significantly better adjusted OS (13.8 vs. 10.0 mo; IPTW HR: 0.66; p = 0.01) and adjusted PFS (4.3 vs. 3.2 mo; IPTW HR: 0.71; p = 0.027) than the NGG. No significant differences were observed in ORR and DCR. The incidence of Grade 3 or worse adverse events did not differ between the two groups except for a high incidence of anemia and diarrhea in the NGG.ConclusionPatients with previous gastrectomy are expected to have better survival outcomes when receiving second‐line irinotecan (IRI)‐based chemotherapy for AGC.

1982P Post hoc analysis of outcomes according to prior chemotherapy (CT) response and platinum agent in the international SAUL study of atezolizumab (atezo) for urinary tract carcinoma (UTC)

1982P Post hoc analysis of outcomes according to prior chemotherapy (CT) response and platinum agent in the international SAUL study of atezolizumab (atezo) for urinary tract carcinoma (UTC)

1260P Efficacy and safety of sunvozertinib in prior platinum treated NSCLC patients with EGFR exon 20 insertion mutations: Primary analysis from the multinational WU-KONG1B pivotal study

1260P Efficacy and safety of sunvozertinib in prior platinum treated NSCLC patients with EGFR exon 20 insertion mutations: Primary analysis from the multinational WU-KONG1B pivotal study

Efficacy and Safety of Salvage-line Nivolumab Monotherapy for Advanced Esophageal Squamous Cell Carcinoma: Comparison of 240 mg Versus 480 mg Doses

BackgroundNivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited.MethodsWe compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line (n = 85) or later-line (n = 32) nivolumab monotherapy at our institution between January 2016 and December 2021.ResultsIn the second-line group, patient characteristics for the 240 mg and 480 mg groups were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2 was 34/61/5% vs. 54/42/4%, and prior fluoropyrimidine plus platinum therapy (FP) was 81.3% vs. 42.3%. In the later-line group, the characteristics were: PS 0/1/2 was 28/60/12% vs. 14/86/0%, and prior FP was 60.0% vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p = 0.19) and 0 vs. 14.3% in the later-line group (p = 0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35–1.01, p = 0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23–1.46, p = 0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively.ConclusionsThe efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.

Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: Primary analysis of the LUMINOSITY trial.

103 Background: Approximately 25% of patients (pts) with non-squamous (NSQ) EGFR wildtype (WT) NSCLC have c-Met protein overexpression (Ansell et al. 2022 CRUK), which is associated with a poor prognosis (Liang, Wang. Onco Targets Ther. 2020). Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the c-Met–overexpressing (OE) NSCLC population best suited to Teliso-V and expand selected group(s) for further evaluation of efficacy. We report on the primary analysis for pts with c-Met OE NSQ EGFRWT NSCLC. Methods: This phase 2, non-randomized, multicenter study enrolled pts with locally advanced/metastatic c-Met OE NSCLC, ≤2 prior lines of therapy (chemotherapy [CTx] + immunotherapy [IO] or sequential CTx + IO), and ≤1 line of chemotherapy. c-Met OE (Ventana MET [SP44] clinical trial assay [CTA]) was defined as ≥25% tumor cells with 3+ staining (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). Teliso-V was dosed at 1.9 mg/kg IV Q2W. Primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: 172 pts with NSQ EGFR WT NSCLC received ≥1 dose of Teliso-V and comprised the safety population; 161 (c-Met high, 78; c-Met int, 83) were included in baseline and efficacy analyses. Median age was 64 yrs (range 33–83), 69% were male, and 70% had ECOG PS 1. 97.5% had prior platinum and 82.0% had prior immune checkpoint inhibitor. Efficacy data are presented in Table below. ORR was 34.6% (c-Met high), 22.9% (c-Met int), 28.6% (overall). Median DOR was 9.0 mo (c-Met high), 7.2 mo (c-Met int), 8.3 mo (overall). Most common any-grade treatment-related AEs (TRAEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade 5 TRAEs occurred in 2 pts (interstitial lung disease, respiratory failure). Conclusions: Teliso-V has shown compelling and durable responses in pts with c-Met OE NSQ EGFR WT NSCLC, especially in pts with c-Met high. Teliso-V had an acceptable safety profile that was clinically manageable, which is consistent with previous data. Clinical trial information: NCT03539536 . [Table: see text]

A phase II trial combining SHR-1316, bevacizumab, and cisplatin/carboplatin in patients with TNBC with active brain metastases.

e13133 Background: Triple-negative breast cancer (TNBC) has a high risk of brain metastases (BM), leading to poor survival. Treatment options for BMs are limited, and the combination of chemotherapy and immune checkpoint inhibitor is the standard-of-care for PD-L1 positive metastatic TNBC. Platinum-based systematic therapy is the mainstay of TNBC treatment and the addition of bevacizumab has shown improvement in the progression-free survival (PFS) of patients with BM. Therefore, this study aims to investigate the efficacy and safety of SHR-1316 (anti-PD-L1) in combination with bevacizumab and cisplatin/carboplatin in TNBC patients with BMs. Methods: In this single-center phase II trial, TNBC patients with active BM received SHR-1316, bevacizumab, and cisplatin/carboplatin. Prior treatment with bevacizumab or anti-PD-1/PD-L1 were not allowed. Prior platinum was allowed only in cases of previous platinum-sensitive response. The primary endpoint was objective response rate (ORR) of central nervous system (CNS), as assessed according to the response assessment in neuro-oncology brain metastases. The secondary endpoint included clinical benefit rate (CBR) of CNS, PFS, overall survival (OS), first progression site and safety. Results: As of January 12th, 2024, a total of 23 female patients with ECOG PS≥1(100%) were enrolled. The median number of previous lines of therapy for metastatic disease was 1 (0-3). All patients had active BM, of which 87% (20/23) were BM treatment-naïve and 13% (3/23) had BM progression after previous local therapy, 26.1% (6/23) had received a prior platinum agent. Of the 23 evaluable patients, the confirmed CNS ORR was 65.2% (95%CI: 42.7%-83.6%), with 3 complete response (CR), 12 partial response (PR), 7 stable disease (SD), and 1 progressive disease (PD). The median CNS-PFS was 11.2 months (95%CI, 5.8 to not reached), median PFS was 7.6 months (95%CI, 5.7-11.9), and median OS was 13.2 months (95%CI, 9.5 to not reached). Treatment-related adverse events (TRAEs) were reported in all 23 patients, and the most common TRAEs were neutrophil count decreased (69.6%, 16/23), anemia (65.2%, 15/23), asthenia (60.9%, 14/23), Hypomagnesaemia (56.5%, 13/23), leukopenia (52.2%, 12/23) and electrocardiogram T wave abnormal (52.2%, 12/23). The incidence of grade ≥3 TRAEs was 43.5% (10/23), including neutropenia (13%, 3/23), platelet count decreased (8.7%, 2/23), and hypertension (8.7%, 2/23). Only one patient had a grade 4 TRAE (lymphocytopenia), and SHR-1316 related serious adverse event (facial nerve disorder) occurred in only one patient. No grade 5 AEs were noted. Conclusions: SHR-1316 plus bevacizumab and cisplatin/carboplatin achieves a significant improvement in CNS ORR and brings PFS and OS benefits in TNBC patients with active BMs. As an effective and safe treatment, this triple-combination warrants further investigation. Clinical trial information: NCT04303988 .

Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer (MBC) with a somatic BRCA1/2mutation identified in a cell-free DNA or tumor tissue genotyping assay.

TPS1143 Background: PARP inhibitors are approved for germline BRCA1/2mutant MBC but the applicability of these well-tolerated oral targeted therapies is limited, as germline BRCA1/2mutations account for 5% of breast cancer. We demonstrated that pathogenic somatic BRCA1/2mutations are detectable in cell-free DNA and tumor tissue genotyping assays in a subset of HER2- MBC, in patients who are not known germline BRCA1/2carriers. In a circulating tumor cell culture model derived from a patient with a pathogenic somatic BRCA1 mutation, we demonstrated that the growth inhibitory effect of a PARP inhibitor paralleled germline BRCA1/2mutant cultures. We hypothesize that somatic BRCA1/2mutations may be amenable to PARP inhibition. In this study, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2mutant MBC. The results may expand the population of patients who benefit from PARP inhibitors. Methods: In this phase II investigator-initiated clinical trial, 30 patients with HER2- MBC with pathogenic somatic BRCA1/2mutations (in the absence of a known germline BRCA1/2mutation) identified in a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are vetted for pathogenicity by genetic counselors using validated genomic databases such as ClinVar. Patients with metastatic triple-negative or hormone receptor positive (HR)+/HER2- breast cancer who received ≥1 prior therapy in the metastatic setting are eligible. Any number of prior therapies are acceptable, including a prior platinum (in absence of disease progression). Patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day until disease progression. Disease assessments occur at baseline and every 3 months via CT chest, abdomen, and pelvis, and bone scan. The primary endpoint is progression free survival (PFS) via RECIST 1.1. This study has 81% power to demonstrate the 12-week PFS is ≥53% (4% alpha). Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory endpoints, determined using serial cell-free DNA collected at baseline and monthly, include identifying resistance mutations, and evaluating the impact of mutant allele fraction and BRCA1/2reversion mutations on response. The Cancer Risk B (CR-B) assay, a novel method to identify double-strand break repair mutations in circulating blood cells, will be correlated with response. The study (NCT03990896) is open at Massachusetts General Hospital, University of California San Francisco, MD Anderson, Emory, Northwestern, and Vanderbilt and will open at Cornell, with 17 patients enrolled as of 2/2024. Clinical trial information: NCT03990896 .

A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: Efficacy and safety analysis (BOLD-100-001).

4059 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in treatment resistant cell lines. Methods: This is a prospective, Phase 2 study. Advanced gastric cancer (GC) patients received BOLD-100 (625 mg/m2) with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate progression free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) of BOLD-100+FOLFOX. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 21 pts with advanced gastric cancer, median age 61 years [range 35, 84] were treated. All patients had stage IV disease and ECOG ≤ 1. Patients had a median of 4 prior systemic therapies [0, 7], 1 with no prior therapy, 2 had 2 prior therapies, 5 with 3 prior therapies, and 13 patients with 4 or more prior therapies. 20/21 patients received prior platinum with 18/21 receiving prior FOLFOX/CAPOX. While on study, pts received a median of 6 cycles BOLD-100 + FOLFOX [range 1-27]. Median PFS and OS was 4.3 [95% credible interval (CI) 2.8, 7.1] months and 7.9 [CI 4.8, 15] months, respectively. ORR was 11% [CI 2, 31] and DCR was 72% [49, 89] in the 18 evaluable patients. Two pts achieved a partial response, 4 pts had target tumor reductions, and 11 pts had stable disease. Treatment was well tolerated. 19 pts had ≥1 treatment-related adverse events (AEs), most commonly neutrophil count decreased (n = 7, 33%), nausea (n = 6, 29%), and peripheral sensory neuropathy (n = 4, 19%). Most AEs were grade (G) 1-2. 7 patients (33%) had G3/4 neutrophil count decreased. Conclusions: BOLD-100 plus FOLFOX is an active, well-tolerated treatment regimen in the heavily pre-treated advanced GC. The reported mPFS, mOS, ORR and DCR data in this analysis shows promising clinical activity. The combination of BOLD-100 with FOLFOX is worthy of further study. Clinical trial information: NCT04421820 .

Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With Previously Treated Metastatic Urothelial Carcinoma: A Phase II Open-Label Study

BackgroundThe PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. Patients and MethodsThis was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. Results22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. ConclusionsAlthough the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

Abstract PO4-19-06: Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping

Abstract Background: PARP inhibitors improve both progression free survival (PFS) and patient quality of life in germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer, leading to their approval in this setting. We have previously shown that a subset of patients with MBC who are not germline BRCA1/2 carriers may harbor pathogenic somatic BRCA1/2 mutations that are identified by cell-free DNA and/or tumor tissue genotyping. In our prior work, we developed a circulating tumor cell culture from a patient with MBC harboring a pathogenic somatic BRCA1 mutation, and demonstrated that a PARP inhibitor induced cell growth inhibition similar to germline BRCA1/2 mutant cultures. Thus, we hypothesize that a PARP inhibitor may be effective in treating somatic BRCA1/2 mutant MBC. In this clinical trial, we are studying the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may help expand the clinical application of PARP inhibitors in MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with MBC who have a pathogenic somatic BRCA1/2 mutation identified by a CLIA certified cell-free DNA and/or tumor tissue genotyping assay. Patients are treated with the PARP inhibitor talazoparib 1 mg/day until progression of disease. Imaging (CT chest, abdomen and pelvis, and bone scan) occurs for disease assessment at baseline and every 3 months. Cell-free DNA is collected at baseline and then monthly to evaluate changes in the genomic environment. Patients also undergo the Cancer Risk B (CR-B) assay, a novel flow variant assay to identify double-strand break repair mutations in circulating blood cells, at baseline. Eligibility Criteria: Patients must have MBC with a pathogenic somatic BRCA1/2 mutation identified in a cell-free DNA and/or tumor tissue genotyping assay, with pathogenicity confirmed by a genetics counselor using validated genomic databases such as ClinVar. Patients may have triple-negative (receipt of at least 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (receipt of at least 1 prior hormone therapy). Patients must not be known germline BRCA1/2 carriers. Any number of prior therapies including a prior platinum (in absence of progressive disease on a platinum) are allowed, but patients should not have received a prior PARP inhibitor. Patients must have adequate organ function and performance status. Specific Aims: The primary aim is to determine PFS (RECIST 1.1). Secondary aims include determining the objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory aims include evaluating serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, understanding the impact of BRCA1/2 reversion mutations in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to understand changes in the genomic environment, studying the CR-B assay positivity rate, and correlating these biomarker analyses with treatment response. Statistical Methods: This study has 81% power to demonstrate that the 12-week PFS is 53% or higher. In contrast, there is a 4% (alpha) probability of concluding that the 12-week PFS is ≥ 53% if the true 12-week PFS is 30% or lower. If 14 or more of 30 total patients achieve PFS > 12 weeks, the null hypothesis (12-week PFS ≤ 30%) will be rejected. Present accrual and target accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, Emory, Northwestern, and Vanderbilt. As of 7/2023, 14/30 patients are enrolled. Funding: This study is funded by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu. Citation Format: Neelima Vidula, Senthil Damodaran, Manali Bhave, Hope Rugo, Ami N. Shah, Erica Blouch, Nathan Royce Ruffle-Deignan, Ogadinma Ogbenna, Lisa E. Flaum, Massimo Cristofanilli, Joseph Sparano, Harry Ostrer, Vandana Abramson, Nora Horick, Aditya Bardia. Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-06.

Durvalumab After Chemoradiotherapy in Patients With Unresectable Stage III Non–Small Cell Lung Cancer

The PACIFIC trial established consolidation durvalumab as the standard of care following chemoradiotherapy (CRT) for patients with unresectable stage III non-small cell lung cancer (NSCLC). Understanding its benefit in routine US clinical practice is critical. To report characteristics, treatment patterns, and outcomes of patients who did or did not receive durvalumab. Two prespecified cohorts were curated in this retrospective cohort study (SPOTLIGHT). Deidentified patient-level data from a US database (Flatiron Health) were analyzed. Patients had unresectable stage III NSCLC, were diagnosed on or after January 1, 2011, had 2 or more visits on or afterward, and received CRT. Data were analyzed from May 2021 to October 2023. Patients started durvalumab after CRT (durvalumab cohort) or ended CRT without durvalumab (nondurvalumab cohort) by June 30, 2019, to allow 15 or more months of follow-up from CRT end. End points included progression-free survival (PFS), overall survival (OS), time to first subsequent therapy or death (TFST), and time to distant metastasis or death (TTDM). The durvalumab cohort included 332 patients (median [IQR] age, 67.5 [60.8-74.0] years; 187 were male [56.3%], 27 were Black [8.7%], 33 were other races [10.7%], and 249 were White [80.6%]) and the nondurvalumab cohort included 137 patients (median (IQR) age, 70.0 [64.0-75.0] years; 89 [65.0%] were male, 11 [8.9%] were Black, 19 [15.4%] were other races, and 93 [75.6%] were White). Most patients had a smoking history (durvalumab, 316 patients [95.2%] and nondurvalumab, 132 patients [96.4%]) and Eastern Cooperative Oncology Group performance status 0 through 1 (durvalumab, 251 patients [90.9%] and nondurvalumab, 88 patients [81.5%]). Median (IQR) CRT duration was 1.6 (1.4-1.8) months for the durvalumab cohort and 1.5 (1.4-1.8) months for the nondurvalumab cohort. Median time to durvalumab discontinuation was 9.5 months (95% CI, 7.8-10.6 months). Median TFST and TTDM were not reached (NR) in the durvalumab cohort and 8.3 months (95% CI, 4.8-11.8 months) and 11.3 months (95% CI, 6.4-14.5 months), respectively, in the nondurvalumab cohort. Median PFS and OS were 17.5 months (95% CI, 13.6-24.8 months) and NR in the durvalumab cohort and 7.6 months (95% CI, 5.2-9.8 months) and 19.4 months (95% CI, 11.7-24.0 months) in the nondurvalumab cohort. In Cox regression analyses of patients who completed concurrent CRT without progression, durvalumab was associated with a lower risk of progression or death (hazard ratio [HR], 0.36; 95% CI, 0.26-0.51) and lower risk of death (HR, 0.27; 95% CI, 0.16-0.43), adjusted for prior platinum agent and patient characteristics. In this cohort study, findings were consistent with PACIFIC, and durvalumab was associated with a lower risk of progression and/or death. Further investigation is warranted to explain why patients did not receive durvalumab after its approval.

Abstract 1169: Increased immunotherapy sensitivity associated with damaging IFN-gamma pathway mutations in NSCLC

Abstract Introduction: In vivo CRISPR screens across multiple murine models of malignancy revealed that loss of interferon gamma (IFN-γ)-mediated sensing predisposes to immune elimination. We assessed the association between damaging mutations in the IFN-γ pathway and clinical outcomes after immune checkpoint inhibition in the Stand Up to Cancer-Mark Foundation non-small cell lung cancer (NSCLC) cohort. Methods: The sensitizing IFN-γ pathway genes were defined as IFNGR1, IFNGR2, JAK1, JAK2, STAT1, IRF1 & IRF9. Damaging mutations (including missense mutations) in any of these genes was considered as loss of pathway activity. We used the best observed response (measured by RECIST v1.1 criteria across time points) to define outcome. Complete and partial response were categorized as responses (R), while stable and progressive disease were categorized as non-responses (NR). The percentage change in target lesions (CTL) was also assessed. Response data was analyzed using additive logistic (LogR) and linear regression (LinR). Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional-hazards models. Three predictor variable groups were established; the final models comprised IFN-γ pathway loss, tumor mutational burden (TMB), programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), prior platinum chemotherapy, age, sex, histological subtype, initial tumor stage, and smoking pack years. Results: 309 patients had evaluable whole-exome sequencing data, treatment with PD-(L)1 inhibitor regimens, and matched radiological responses (121 R [39%], 188 NR [61%]); 306 had matched OS data; 297 had matched PFS data; and 227 had matched CTL data. 27 (7%) patients had damaging mutations in the IFN-γ pathway [IFNGR1 (3); IFNGR2 (1); JAK1 (6); JAK2 (8); STAT1 (3); IRF1 (1); IRF9 (3); and JAK2 & IRF9 (1)]. Significant relationships were observed in univariable models between IFN-γ pathway loss and both response (LogR: OR 0.17, p=2 × 10−4*; LinR: OR 0.70, p=4.8 × 10−4*) and survival (PFS: HR 0.45, p=0.0067*; OS: HR 0.51, p=0.037*). IFN-γ pathway loss is significantly associated with TMB (p=9.7 × 10−8*, Wilcoxon signed rank test). Multivariable models incorporating TMB and PD-L1 TPS confirmed the significance of IFN-γ pathway loss in both response (LogR: OR 0.29, p=0.050*; LinR: OR 0.71, p=0.0052*) and survival (PFS: HR 0.37, p=0.036*; OS: HR 0.27, p=0.030*). These relationships persisted in the final multivariable models (LogR: OR 0.32, p=0.11; LinR: OR 0.69, p=0.012*; PFS: HR 0.39, p=0.068; OS: HR 0.15, p=0.0038*). Random gene sets, of similar total protein coding sequence length, significantly associated with TMB but not with multivariable models of response or survival. Conclusion: In this NSCLC cohort, damaging IFN-γ pathway mutations associate with increased immunotherapy sensitivity, independently of TMB and other co-variates, as evidenced by multiple clinical outcomes. Citation Format: Alexander Azizi, Arvind Ravi, Natalie Vokes, Stephen-John Sammut, Justin Gainor, Gad Getz. Increased immunotherapy sensitivity associated with damaging IFN-gamma pathway mutations in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1169.

A real-world study of treatment patterns following disease progression in epithelial ovarian cancer patients undergoing poly-ADP-ribose polymerase inhibitor maintenance therapy

BackgroundThe efficacy of subsequent therapy after poly-ADP-ribose polymerase (PARP) inhibitor maintenance treatment has raised concerns. Retrospective studies show worse outcomes for platinum-based chemotherapy after progression of PARP inhibitor-maintenance therapy, especially in BRCA-mutant patients. We aimed to describe subsequent therapy in ovarian cancer patients after PARP inhibitor-maintenance therapy and evaluate their response to treatment. We focused on chemotherapy for patients with a progression-free interval (PFI) of ≥ 6 months after prior platinum treatment, based on BRCA status.MethodsWe analyzed real-world data from Peking University Cancer Hospital, subsequent therapy after progression to PARP inhibitor-maintenance therapy for epithelial ovarian cancer between January 2016 and December 2022. Clinicopathological characteristics and treatment outcomes were extracted from medical records. The last follow-up was in May 2023.ResultsA total of 102 patients were included, of which 29 (28.4%) had a germline BRCA1/2 mutation and 73 (71.6%) exhibited BRCA1/2 wild-type mutations. The PARP inhibitors used were Olaparib (n = 62, 60.8%), Niraparib (n = 35, 34.3%), and others (n = 5, 4.9%). The overall response rate (ORR) was 41.2%, and the median time to second progression (mTTSP) was 8.1 months (95%CI 5.8–10.2). Of 91 platinum-sensitive patients (PFI ≥ 6 months) after progression to PARP inhibitor-maintenance therapy, 65 patients subsequently received platinum regimens. Among them, 30 had received one line of chemotherapy before PARP inhibitor-maintenance therapy. Analysis of these 30 patients by BRCA status showed an ORR of 16.7% versus 33.3% and mTTSP of 7.1 (95% CI 4.9–9.1) versus 6.2 months (95% CI 3.7–8.3, P = 0.550), for BRCA-mutant and wild-type patients, respectively. For the remaining 35 patients who had received two or more lines of chemotherapy before PARP inhibitor-maintenance therapy, ORR was 57.1% versus 42.9%, and mTTSP was 18.0 (95% CI 5.0–31.0) versus 8.0 months (95% CI 4.9–11.1, P = 0.199), for BRCA-mutant and wild-type patients, respectively.ConclusionNo differences in survival outcomes were observed among patients with different BRCA statuses. Furthermore, for patients who had undergone two or more lines of chemotherapy before PARP inhibitor maintenance therapy, no negative effects of PARP inhibitors on subsequent treatment were found, regardless of BRCA status.

Abstract B035: Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer

Abstract B035: Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer

Abstract C064: Chronic platinum exposure induces cell-intrinsic type1 interferon/STING pathway activation in homologous recombination-deficient pancreatic cancer to drive sensitivity to checkpoint immunotherapy

Abstract Background: Although platinum-based chemotherapy is standard treatment for pancreatic ductal adenocarcinoma (PDAC) patients with germline/somatic mutations in homologous recombination (mutHRD), a subset become platinum-resistant. We have shown that patients with mutHRD PDAC progressing on platinum chemotherapy respond to dual immune checkpoint blockade (ICB) with anti-PD1+CTLA-4. We sought to model these clinical findings in preclinical models to interrogate mechanisms in platinum-resistant mutHRD PDAC that drive ICB sensitivity. Methods: We examined the association between objective disease response following anti-PD1+CTLA-4 ICB and duration of platinum chemotherapy exposure in platinum-resistant mutHRD PDAC patients. Cisplatin- resistant and sensitive Brca2-silenced (via shRNA knockdown) KPC cancer cells were generated and characterized in vitro and in vivo. Results: In 12 mutHRD PDAC patients treated with salvage dual ICB after progression on platinum-based chemotherapy, 7 (58%) demonstrated either partial response or stable disease. Notably, duration of prior platinum exposure was associated with post-ICB disease response. To model these findings preclinically, syngeneic mice implanted with cisplatin-sensitive or resistant shBrca2 or wildtype KPC tumor cells and subsequently treated with gemcitabine+cisplatin chemotherapy demonstrated expected rapid tumor growth of cisplatin-resistant shBrca2 tumors. However, we observed a profound reduction in tumor volumes when these chronically cisplatin-resistant KPC-shBrca2 tumors were subsequently treated with anti-PD-1+CTLA4 ICB, compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumors (P<0.001). To understand mechanistic underpinnings of these observations, whole transcriptome sequencing revealed significant differential upregulation of type1 interferon and cGAS-STING pathways in cisplatin-resistant KPC-shBrca2 tumor cells compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 controls (P-adj≤0.05). Confocal immunofluorescence imaging confirmed constitutively upregulated cGAS and STING expression in cisplatin-resistant KPC-shBrca2 compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumor cells. Activation of type1 interferon/STING manifested in a secretome enriched for T-cell trafficking cytokines CXCL10, CXCL9, and CCL5 from cisplatin-resistant KPC-shBrca2 cells. Intriguingly, evaluable mutHRD patient tumors responsive to dual ICB also demonstrated baseline increase in CXCL9/10 and CCL5 expression compared with ICB-resistant mutHRD tumors (n=3 each) via Nanostring analysis. As such, we observed increased transwell (in vitro) and intratumoral (in vivo) CD8+ T-cell trafficking to cisplatin-resistant KPC-shBrca2 tumors compared with cisplatin-sensitive KPC-shBrca2 controls. Conclusions: Chronicity of platinum exposure in mutHRD PDAC potentiates ICB sensitivity via induction of cell-autonomous type-1 interferon/cGAS-STING signaling and ensuing T-cell trafficking to the PDAC tumor microenvironment. Citation Format: Ifeanyichukwu Ogobuiro, Anna Bianchi, Lucas Caeiro, Haleh Amirian, Luis Nivelo, Iago De Castro Silva, Karthik Rajkumar, Andrew Adams, Vanessa Garrido, Samara Singh, Nagaraj Nagathihalli, Nipun Merchant, Ramiro Verdun, Peter Hosein, Jashodeep Datta. Chronic platinum exposure induces cell-intrinsic type1 interferon/STING pathway activation in homologous recombination-deficient pancreatic cancer to drive sensitivity to checkpoint immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C064.

CTLA-4 Blockade Results in the Enrichment of Proliferative CD56 dimCD16 + NK Cells Following Infusion of Haploidentical Donor Memory-like Natural Killer Cells Plus IL-15 Superagonist in a Phase 1 Trial

Introduction Regulatory T cells (Tregs) blunt anti-tumor responses of major immune effector cells including CD8 T cells and natural killer (NK) cells. Tregs constitutively express CTLA-4 and thus the use of ipilimumab, a CTLA-4 blocker can potentially overcome the Treg-mediated immune suppression. We (and others) have shown that a brief activation of conventional NK cells with the cytokine combination IL-12, IL-15, and IL-18 generates cytokine-induced memory-like (CIML) NK cells which exhibit enhanced anti-tumor responses, have a longer half-life (up to 90 vs ~12 days of conventional NK cells), and show promising activity in several early phase clinical trials. N-803 is an IL-15 super-agonist with a long half-life that preferentially activates and expands NK and CD8+ T cells without affecting Tregs, making it an ideal cytokine for combining with adoptive immunotherapy. In the current study, we hypothesized the use of ipilimumab (IPI) will abrogate Treg-mediated inhibition and thus allow enhanced proliferation, activation, and anti-tumor responses of the adoptively transferred CIML NK cells.To address this, we conducted a phase 1 trial of HLA-haploidentical CIML NK cells in combination with IPI and N-803 in patients with advanced head and neck cancer (HNC). Using flow cytometry and CITE-Seq on the banked peripheral blood samples, we performed an in-depth characterization of NK cells expanded following IPI pre-exposure and compared it to those who did not receive IPI. Methods We enrolled 10 patients with refractory HNC regardless of human papillomavirus (HPV) status who had prior platinum and immunotherapy (NCT04290546). All patients received lymphodepletion with fludarabine (25 mg/m 2 x 5 days) and cyclophosphamide (60 mg/kg x 2 days) during days -6 to -2 prior to haploidentical CIML NK cell infusion on day 0 (5-10 x 10 6 cells/kg=dose level 0) followed by N-803 (15 mcg/kg subcutaneously) starting on day +1 every 21-days for 4-doses. In cohort 2, patients received IPI (3 mg/kg) on day -7, no ipilimumab was given to the first 6 patients treated on the lead-in safety cohort 1. Flow cytometry using a custom NK cell panel was performed on samples collected on days +7, +14, +21, +28, +42, and +60 after CIML NK cell infusion. FlowSOM clustering was performed on NK cell markers. UMAP clustering was applied to CITE sequencing data acquired from samples collected on day +7 and day +28, and well-defined markers genes for each cluster were used to identify cell populations. NK cell function (cytotoxicity, IFNg, and CD107a) was assessed using flow-cytometry based assays. Results The median age of the patients was 58, 90% were men and 80% had oropharyngeal primaries. Mild CRS (grade 2 or lower) was observed in 60% of patients. No neurotoxicity or graft-versus-host disease was observed. Maximal expansion of NK cells occurred on day +7 following CIML NK cell infusion in 9/10 of patients. The single patient without NK cell expansion was found to have a donor-specific anti-HLA antibody. Day +7 NK cells exhibited upregulation of IFNg expression following cytokine restimulation as compared to resting NK cells. Tumor regression was observed in 50% of treated patients at day +30 based on RECIST v1.1 criteria. Patients who had tumor regression had an expansion of CD56 dimCD16 + NK cell clusters by day +14. IPI treated patients were noted to have a relative enrichment of CD16 + NK cell metaclusters at day +14 compared to no IPI patients (Figure 1A). At the time of maximal NK cell expansion, CITEseq defined NK cell clusters were dominant in both IPI and no IPI patients, but the proliferative gene sets were enriched in the IPI treated patient (Figure 1B). IPI exposure had no effect on the distribution of regulatory T cells or CD8 + T cell populations at day +28 compared to the no IPI patients. Conclusions The use of donor-derived CIML NK cells is safe and associated with tumor regression in patients with advanced HNC. The use of IPI was associated with the preferential expansion of CD16 + NK cell clusters that had enrichment of proliferative gene sets. Tumor regression was associated with CD56 dimCD16 + NK cell expansion. Further work is required to elucidate the mechanism by which IPI exposure is associated with the expansion of specific subsets of CIML NK cells.

Efficacy and safety of utidelone for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have failed standard second-line treatment: A phase 2 clinical trial (BG01-1801)

BackgroundChemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC), but acquired resistance presents challenges. The aim of this open-label, multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone, a novel genetically engineered epothilone analog and microtubule-stabilizing agent, as a third- or later-line treatment for locally advanced or metastatic NSCLC. MethodsPatients who had failed standard second-line treatment (including platinum-containing chemotherapy or targeted therapy) received utidelone (40 mg/m2 via intravenous injection daily, day 1–5) every 21 days. The primary endpoint was the objective response rate (ORR). Secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. ResultsFrom March 12, 2019 to January 18, 2021, 26 pretreated patients with locally advanced or metastatic NSCLC (100% of patients had received prior platinum and 65.4% patients had received prior taxane treatment) were enrolled (80.8% of patients had adenocarcinoma). At baseline, nine (34.6%) patients had received second-line treatment, 10 (38.5%) patients had received third-line treatment, and seven (26.9%) patients had received fourth- or later-line treatment. By the data cut-off date of August 10, 2021, the median follow-up was 7.49 months (range, 1.4–26.7 months). The ORR was 15.4% (95% confidence interval [CI], 4.4%–34.9%) in the intention-to-treat (ITT) cohort (N = 26) and 19.0% (95% CI, 5.4%–41.9%) in the per-protocol (PP) cohort (N = 21). The disease control rate was 69.2% (95% CI, 48.2%–85.7%) and 81.0% (95% CI, 58.1%–94.6%) in the ITT and PP cohorts, respectively. The median DoR was 4.1 months (95% CI, 3.1–5.1 months) in the ITT cohort. The median PFS was 4.37 months (95% CI, 2.50–5.29 months) in the ITT cohort and 4.37 months (95% CI, 2.50–9.76 months) in the PP cohort. The median OS was not reached, and the 12-month OS rate was 69% (95% CI, 45.1%–84.1%). Grade 3/4 treatment-emergent adverse events occurred in 38.5% of patients, and the most common was peripheral neuropathy (23.1%, all Grade 3), which was manageable with dose modifications. ConclusionsIn this clinical trial, utidelone showed promising efficacy and had a manageable safety profile. Further clinical studies are warranted to confirm its role in NSCLC treatment. Trial registrationNo.NCT03693547; https://classic.clinicaltrials.gov.

Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer.

Amivantamab has demonstrated durable responses with a tolerable safety profile in non-small cell lung cancer with EGFR exon 20 insertions (Ex20ins) who progressed after prior platinum chemotherapy. Data supporting the amivantamab recommended phase II dose (RP2D) in this patient population are presented. Pharmacokinetic (PK) analysis and population PK (PopPK) modeling were conducted using serum concentration data obtained following amivantamab intravenous administration (140-1,750 mg). Pharmacodynamics (PDs) were evaluated using depletion of soluble EGFR and MET. Exposure-response (E-R) analyses were performed using the primary efficacy end point of objective response rate in patients with EGFR Ex20ins. The E-R relationship for safety was explored for adverse events of clinical interest. Amivantamab exhibited linear PKs at 350-1,750 mg dose levels following administration, with no maximum tolerated dose identified. A two-compartment PopPK model with linear clearance adequately described the observed PKs. Body weight was a covariate of clearance and volume of distribution in the central compartment. PopPK modeling showed that a weight-based, 2-tier (< 80 and ≥ 80 kg) dosing strategy reduces PK variability and provides comparable exposure across 2 weight groups, with 87% of patients achieving exposures above the target threshold. The final confirmed RP2D of amivantamab was 1,050 mg for < 80 kg (1,400 mg for ≥ 80 kg) weekly in cycle 1 (28 days) and every 2 weeks thereafter. No significant exposure-efficacy or safety correlation was observed. In conclusion, the amivantamab RP2D is supported by PK, PD, safety, and efficacy analyses. E-R analyses confirmed that the current regimen provides durable efficacy with tolerable safety.

2380P Real-world effectiveness of single agent enfortumab vedotin (EV) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) based on line of therapy and impact of prior platinum (plat) chemotherapy (chemo) and PD-1/PD-L1 inhibitors (PD-1/PD-L1i)

2380P Real-world effectiveness of single agent enfortumab vedotin (EV) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) based on line of therapy and impact of prior platinum (plat) chemotherapy (chemo) and PD-1/PD-L1 inhibitors (PD-1/PD-L1i)

Harnessing olaparib, palbociclib, and endocrine therapy: A phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA mutation-associated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HOPE).

TPS1126 Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) in patients (pts) with germline or somatic BRCA1 or BRCA2 (g/s BRCA1/2) mutations has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial showed superiority of fulvestrant (F) with palbociclib (P) compared to F alone. The OlympiAD trial showed the poly-ADP ribose polymerase inhibitor (PARPi) olaparib (O) to be superior to chemotherapy in BRCA1/2-associated MBC. However, treatment resistance inevitably develops; targeting dual therapeutic drivers concurrently may delay or circumvent resistance. O and P have overlapping hematologic toxicity and the safety of combined O, P and F is unknown. The tolerability of O + P is particularly relevant given the emergence of potentially less myelosuppressive PARPi. Methods: HOPE (NCT03685331) is a phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/s BRCA1/2-associated, HR+ MBC. Eligible pts have an ECOG performance status 0-1, measurable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 lines of chemotherapy for MBC. Prior platinum is allowed for curative intent if completed at least 12 months prior to MBC diagnosis, or for MBC if no progression during therapy. Prior PARPi and CDK4/6i are permitted on phase I, and are permitted during phase II if there was no progression on them. Treatment (28-day cycles) consists of: O orally twice daily continuously; F 500mg intramuscularly on day 1 of each cycle plus load; and P orally once daily on days 1-21. Phase I begins with a 28-day safety run-in of O and F alone. O and P doses are based on dose level (DL): DL 0 (starting level), O 300mg, P 75mg; DL 1, O 300mg, P 100mg; DL 2, O 300mg, P 125mg; DL-1, O 250mg, P 75mg and DL-2, O 200mg, P 75mg. For phase II, O and P will be dosed at MTD. Pts have tissue collection at baseline and peripheral blood cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). Phase I primary endpoint is MTD. A 3+3 dose escalation design is used with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. A minimum of 2 and a maximum of 18 patients will be enrolled on the phase I. Phase II primary endpoint is PFS using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. Phase II will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with O monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment is ongoing. Clinical trial information: NCT03685331 .