Achieved Objective Response Research Articles

Preliminary results of a phase II trial with sacituzumab govitecan-hziy in patients with recurrent endometrial carcinoma overexpressing Trop-2.

5599 Background: Despite recent advances, there remains a significant need for targeted, efficacious treatments for advanced and recurrent endometrial carcinoma (EC). Trop-2 has been demonstrated to be overexpressed in several EC including grade 3 endometrioid adenocarcinoma (96%), and uterine serous carcinoma (65%). Trop-2 overexpression has been found to confer a worse prognosis and predicts disease recurrence. Sacituzumab govitecan-hziy (SG) is an antibody-drug conjugate comprised of a humanized anti-Trop-2 antibody conjugated with the active metabolite of irinotecan, a topoisomerase-I inhibitor. SG is currently FDA-approved for use in metastatic urothelial cancer and metastatic triple-negative breast cancer. Methods: We report results from the stage 1 of an open-label non-randomized phase 2 trial (NCT04251416) established to evaluate the clinical activity of SG in patients with persistent or recurrent EC of epithelial origin with Trop-2 overexpression. Criteria for study participation included radiographically confirmed and measurable persistent or recurrent EC, progression after or during platinum-based chemotherapy, and at least 2+ staining of Trop-2. One target lesion by RECIST v1.1 and adequate bone marrow, renal, and hepatic function were required. Patients were at least two weeks beyond prior treatment, major surgery, or high dose systemic corticosteroid use. Patients were given 10mg/kg of SG administered as an intravenous infusion once weekly on days 1 and 8 of 21-day treatment cycles. This 3-week cycle was continued without rest until disease progression or unacceptable toxicity. Results: Twenty-one patients were enrolled into stage 1. Ten patients (48%) had uterine serous carcinoma, seven (33%) had endometrioid adenocarcinoma, three (14%) had carcinosarcoma, and one patient had mixed serous and clear cell histology. All patients received at least one prior line of chemotherapy, (median 3 lines, range 1-6). At the time of submission, 20 patients were response-evaluable (Table); seven (35%) achieved objective response (5 out of 7 confirmed). Eighteen patients were evaluable for durable disease control; 7 (39%) achieved it. Follow-up durations had a median (IQR) of 15.6 (5.7–22.5) months. Median OS was 22.5 months, and median PFS was 5.7 months. The treatment was well-tolerated with no new or unexpected safety signals reported. Conclusions: Sacituzumab govitecan shows remarkable clinical activity against some of the most historically challenging and chemotherapy-resistant endometrial pathologies and demonstrates a favorable safety profile. With these promising results, we will begin the stage 2 expansion of this phase 2 trial. Clinical trial information: NCT04251416 . [Table: see text]

Abstract 526: RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers

Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with the highest prevalence in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). RMC-9805 is a first-in-class, oral, mutant-selective covalent inhibitor of the GTP-bound and active RAS(ON) form of KRASG12D. The formation of a stable, high affinity tri-complex between RMC-9805, KRASG12D and cyclophilin A results in the suppression of signaling downstream of KRASG12D(ON) by disrupting its interactions with downstream effectors such as RAF kinases. RMC-9805 treatment caused selective and persistent modification of KRASG12D leading to deep and durable suppression of RAS pathway activity, inhibition of cell proliferation, and apoptosis induction in KRASG12D human cancer cell lines in vitro and tumor models in vivo. In a mouse clinical trial with KRASG12D xenograft tumor models, RMC-9805 administered orally as a single agent was well tolerated and induced objective responses in 7 of 9 PDAC PDX and CDX models and 6 of 9 NSCLC PDX models, as assessed by mRECIST. In the few models that exhibited sub-optimal responses to RMC-9805 monotherapy, combination treatment with various RAS Companion Inhibitors improved depth and/or duration of anti-tumor response. In contrast to RASMUTANT NSCLC and PDAC, CRC tumors are less dependent on RAS driver mutations. For example, a more heterogeneous response to KRASG12C inhibitors has been reported in CRC than in NSCLC patients, suggesting combinations will be desired to achieve significant clinical benefit in CRC. Likewise, RMC-9805 monotherapy is less active in CRC models at doses that were highly active in KRASG12D NSCLC and PDAC models. However, combinations of RMC-9805 with vertical or parallel pathway RAS Companion Inhibitors such as SHP2, mTORC1 or RASMULTI(ON) inhibitors, achieved objective response rates up to 60% and delayed the onset of resistance in tumor models in vivo. RMC-9805 also synergized with anti-PD1 therapy in KRASG12D tumors in immune-competent animal models by shaping a favorable tumor immune microenvironment through cytokine modulation. In addition, RMC-9805 engaged the adaptive immune system by increasing presentation and recognition of tumor antigens, promoting a diversification of the TCR repertoire, and inducing immunological memory. Overall, RMC-9805 monotherapy elicited tumor regressions in most preclinical PDAC and NSCLC cancer models harboring KRASG12D. Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors. Citation Format: Lingyan Jiang, Marie Menard, Caroline Weller, Zhican Wang, Les Burnett, Ida Aronchik, Shelby Steele, Mike Flagella, Ruiping Zhao, James W W. Evans, Shook Chin, Kang-Jye Chou, Yunming Mu, Michael Longhi, Laura McDowell, John E. Knox, Adrian Gill, Jacqueline A. Smith, Mallika Singh, Elsa Quintana, Jingjing Jiang. RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 526.

Improved Survival of Patients with Primary Plasma Cell Leukemia with VRd or Daratumumab-based Quadruplets: A Multicenter Study by the Greek Myeloma Study Group.

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) vs. previous anti-myeloma therapies i.e., bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria i.e. circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001-2021, were studied; 37% had cPCS 5-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective response. Treatment with VRd/DBQ strongly correlated with higher complete response rate (41% vs. 17%; p=0.008). After a median follow up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p=0.03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < 0.001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/μL, independently predicted for OS (p < 0.05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL. This article is protected by copyright. All rights reserved.

For Hepatocellular Carcinoma Treated with Yttrium-90 Microspheres, Dose Volumetrics on Post-Treatment Bremsstrahlung SPECT/CT Predict Clinical Outcomes.

In transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) with Yttrium-90 (Y-90) microspheres, recent studies correlate dosimetry from bremsstrahlung single photon emission tomography (SPECT/CT) with treatment outcomes; however, these studies focus on measures of central tendency rather than volumetric coverage metrics commonly used in radiation oncology. We hypothesized that three-dimensional (3D) isodose coverage of gross tumor volume (GTV) is the driving factor in HCC treatment response to TARE and is best assessed using advanced dosimetry techniques applied to nuclear imaging of actual Y-90 biodistribution. We reviewed 51 lobar TARE Y-90 treatments of 43 HCC patients. Dose prescriptions were 120 Gy for TheraSpheres and 85 Gy for SIR-Spheres. All patients underwent post-TARE Y-90 bremsstrahlung SPECT/CT imaging. Commercial software was used to contour gross tumor volume (GTV) and liver on post-TARE SPECT/CT. Y-90 dose distributions were calculated using the Local Deposition Model based on post-TARE SPECT/CT activity maps. Median gross tumor volume (GTV) dose; GTV receiving less than 100 Gy, 70 Gy and 50 Gy; minimum dose covering the hottest 70%, 95%, and 98% of the GTV (D70, D95, D98); mean dose to nontumorous liver, and disease burden (GTV/liver volume) were obtained. Clinical outcomes were collected for all patients by chart and imaging review. HCC treatment response was assessed according to the modified response criteria in solid tumors (mRECIST) guidelines. Kaplan-Meier (KM) survival estimates and multivariate regression analyses (MVA) were performed using STATA. Median survival was 22.5 months for patients achieving objective response (OR) in targeted lesions (complete response (CR) or partial response (PR) per mRECIST) vs. 7.6 months for non-responders (NR, stable disease or disease progression per mRECIST). On MVA, the volume of underdosed tumor (GTV receiving less than 100 Gy) was the only significant dosimetric predictor for CR (p = 0.0004) and overall survival (OS, p = 0.003). All targets with less than CR (n = 39) had more than 20 cc of underdosed tumor. D70 (p = 0.038) correlated with OR, with mean D70 of 95 Gy for responders and 60 Gy for non-responders (p = 0.042). On MVA, mean dose to nontumorous liver trended toward significant association with grade 3+ toxicity (p = 0.09) and correlated with delivered activity (p < 0.001) and burden of disease (p = 0.05). Dosimetric models supplied area under the curve estimates of > 0.80 predicting CR, OR, and ≥grade 3 acute toxicity. Dosimetric parameters derived from the retrospective analysis of post-TARE Y-90 bremsstrahlung SPECT/CT after lobar treatment of HCC suggest that volumetric coverage of GTV, not a high mean or median dose, is the driving factor in treatment response and that this is best assessed through the analysis of actual Y-90 biodistribution.

Improved Survival of Patients with Primary Plasma Cell Leukemia with VRD or Daratumumab-Based Quadruplets: A Multicenter Study By the Greek Myeloma Study Group

Primary plasma cell leukemia (pPCL) is a rare plasma cell disorder with poor outcome. Recently, the International Myeloma Working Group revised its definition proposing cPCS of ≥5% as the new cut-off value. There is still limited information regarding the impact of novel effective anti-myeloma combinations, i.e., bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) on pPCL outcome. Therefore, considering the lack of prospective trials, our aim was to compare retrospectively treatment approaches, and to evaluate prognostic factors of overall survival (OS) in an extended cohort of pPCL patients including those fulfilling the new criteria, in the real-world setting. We analyzed the medical records of 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86; IgG: 47, IgA: 17, light-chain: 32, IgD: 3, IgM: 2, non-secretory: 9; ISS1: 9, ISS2: 32, ISS3: 69) out of 3324 myeloma patients (3%), registered in our database, between 2001-2021; 51% of patients were ≤65 years; Eastern Cooperative Group (ECOG) was ≥2 in 46%; 65% had advanced bone disease and 15% had bone/soft tissue plasmacytomas; 72% had Bence-Jones proteinuria, 45% had abnormal LDH, 27% had hypercalcemia, 72% had hemoglobin <10 g/dL and 24% had estimated glomerular filtration rate <30ml/min/1.73m2. High-risk molecular abnormalities i.e., del17p, t(4;14), t(14;16) and 1q21+ tested by FISH hybridization were detected in 56%; 30% had t(11;14). Revised ISS (RISS) was distributed as follows: RISS1: 4%, RISS2: 58%, RISS3: 38%. Median cPCs % was 11% (range: 5-71%), in line with multiparameter flowcytometry findings (10%; range: 4,5-71%). Immunophenotype of PCs was similar in bone marrow and peripheral blood in 92% of patients; CD56(-) and CD27(+) cPCs was found in 52% and 35%, respectively. 37% had cPCS 5-20%; Patients' characteristics did not correlate with cPCs %, except from platelets (PLT) that were significantly lower in patients with >20% cPCs; 89% of patients received novel therapies; DBQ: 21%, VRd: 16%, bortezomib standard combinations (BSC): 52%, conventional chemotherapy (CT): 11%; 35% underwent autologous stem cell transplantation (ASCT). Regarding response to treatment 83% achieved objective response (≥PR); 24% had very good partial response (vgPR), and 26% had complete response (CR). Median time to response was one month (range 1-5). Treatment with VRd/DBQ or ASCT strongly correlated with higher CR rates (45% vs. 19%; p=0.007; 52% vs. 11%; p<0.001, respectively). After a median follow up of 51 months (95% CI: 45-56), 67 patients died (progression: 42, infection: 20, other: 5) and 43 patients remain alive. Early mortality (≤1 month) occurred in 4/67 deceased patients; 51/110 (46%) patients received 2nd line therapy (lenalidomide-based: 17, proteasome inhibitor-based: 12, daratumumab-based: 9, pomalidomide-based: 4, CT: 9). Median number of treatment lines was 1 (range: 1-5). Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (25 months 95% CI: 13.5-36.5, vs. 13 months 95% CI: 9-16.8; p=0.03). Median OS was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p<0.001; HR: 3.88). Median survival after pPCL progression was 8 months (95% CI: 3.5-13.5). In the univariate analysis, ECOG ≥2, PLT <100.000/μL, cPCs (5-20% vs >20%), del17p(+), upfront treatment with VRd/DBQ, ASCT and CR were independent prognostic factors for OS; treatment with VRd/DBQ, del17p(+) and PLT <100.000/μL, significantly predicted for OS in the multivariate analysis (p<0.05). Median OS for patients with del17p(+) vs. del17p(-) was 17 months (95% CI: 11.7-22) vs. 48 months, respectively (95% CI: 27.8-68) (p=0.01, HR: 3.1). Median OS for patients with PLT <100.000/μL vs. ≥100.000/μL was 16 months (95% CI: 9-23) vs. 46 months (95% CI: 28-64) respectively (p=0.01; HzR: 0.34). These real-world data, based on the largest reported national multicenter series of pPCL incorporating the new criteria, has shown that treatment with VRd or antiCD38-based quadruplets induces deep and durable responses and is one of the strongest prognostic factors for OS representing currently the best therapeutic approach for pPCL; ASCT maintained its therapeutic value. Del17p (+) and thrombocytopenia were negative predictors for OS.

1456P Long-term survivorship rates for first-line intermediate or poor (I/P) risk advanced renal cell carcinoma (aRCC) patients achieving objective response (OR) with nivolumab plus ipilimumab (N+I)

Long-term (minimum 60-month) follow-up from the CheckMate 214 study showed high OR rate (42%) and durable response benefits with a yet to be reached median duration of response (DoR) for I/P risk aRCC patients treated with N+I. This led to sustained survival plateaus implying the possibility of long-term survivors (LTS), which can be estimated via mixture cure models (MCMs).

Dynamic changes in serum analyte levels associated with clinical outcome in squamous cell lung cancer trial SWOG Lung-MAP S1400I of nivolumab ± ipilimumab.

9044 Background: While Immune checkpoint blockade (ICB) is standard treatment for lung cancer there are limited biomarkers that predict benefit, pharmacokinetic on-treatment activity or explain progression. S1400I was a randomized Phase III trial of nivolumab(N)+ipilimumab(I) versus N (NCT02154490, PMID 34264316) for ICB naïve, previously treated stage IV or recurrent squamous cell lung cancer. We performed circulating serum protein analysis of serial blood specimens from patients enrolled in S1400I to evaluate if serum proteins levels changed over time, changes differed by treatment arm, and if they were associated with overall survival. Methods: 561 serial blood specimens (baseline, weeks (wk) 3, 7, 9, and progression [PD]) from 160 of 252 eligible patients enrolled to S1400I were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized with use of internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (wks 3,7,9 and PD), and NPX differences at baseline, wk3, and PD depending on best objective response. A Cox model was used to evaluate the association between baseline NPX and survival. Overall survival and longitudinal cytokine expression were jointly modeled using a linear mixed model to estimate dynamic biomarker changes in NPX and a Cox model for survival. The joint models for time-varying NPX values included a random intercept and modeled time using a natural spline with three knots. Significance was defined as P &lt; 0.05. Results: Serum proteins PCDC1, CXCL9, and CXCL10 were increased from baseline at wks 3,7,9 and at PD. CCL19 was increased at wks 3 and 7 but not at wk 9 and PD. IL10 and IFNγ were increased at wk 3 but subsequently returned to baseline. Change in CXCL13 from baseline to PD was larger for N+I versus N. Baseline CCL23, CSF-1, IL6, and MUC-16 were associated with shorter survival (HR &gt; 1). Joint modeling of survival with cytokines showed an increased risk of death (HR &gt; 1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL8. Patients achieving objective response had higher IL4 and LAMP3 and lower IL6 and IL8 at baseline and wk 3 compared to non-responders. Conclusions: Measurements of blood circulating soluble proteins represent easily accessible biomarkers that may be useful as indicators of outcome, and that will need to be prospectively confirmed. Clinical trial information: NCT02154490.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle=28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Lorlatinib for Previously Treated ALK-Positive Advanced NSCLC: Primary Efficacy and Safety From a Phase 2 Study in People’s Republic of China

IntroductionLorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC. MethodsOpen-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1: previous crizotinib; cohort 2: one ALK tyrosine kinase inhibitor other than crizotinib [±prior crizotinib]), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point: objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose. ResultsAt data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1: n = 67; cohort 2: n = 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval [CI]: 57.7–80.7, p < 0.0001; primary end point) and 20 patients in cohort 2 (47.6%, 95% CI: 32.0–63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI: 64.0–91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI: 25.7–70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs; one permanently discontinued from treatment because of TRAEs. ConclusionsLorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

Post hoc analysis of the efficacy of pembrolizumab retreatment after progression of advanced urothelial carcinoma (UC) in KEYNOTE-045 and KEYNOTE-052.

512 Background: Pembrolizumab (pembro) has shown efficacy in advanced/unresectable and metastatic UC (mUC). There is interest in determining whether pts should be treated subsequently with checkpoint inhibitors such as anti–PD-1 therapy if mUC responds then later progresses. Pembro retreatment after disease progression has shown efficacy in melanoma and NSCLC. This post hoc exploratory analysis investigated the efficacy of pembro retreatment for pts with advanced UC or mUC enrolled in KEYNOTE-045 and KEYNOTE-052 with a best overall response (BOR) of SD or better and whose disease progressed after discontinuation or completion of 2 y of therapy. Methods: The phase 3 KEYNOTE-045 trial (NCT02256436) was designed to compare the efficacy and safety of pembro vs chemotherapy (chemo) in pts with mUC that recurred/progressed on platinum containing chemo; ≤2 prior lines of systemic chemo for mUC were permitted. The phase 2 KEYNOTE-052 trial (NCT02335424) was designed to evaluate the efficacy and safety of first-line pembro in cisplatin-ineligible pts with advanced UC. In both studies, pembro was administered for up to 2 y; pts were eligible for retreatment if they stopped pembro after CR or had a BOR of CR, PR, or SD and completed 2 y of treatment. Pts must have investigator-confirmed radiographic PD after therapy cessation, have ECOG PS score 0-1, and not have received anticancer treatment after the last pembro dose. BOR to retreatment is reported. Results: At data cutoff for KEYNOTE-045 (Oct 1, 2020), 11 pts were retreated: 5 (45%) achieved objective response to retreatment (3 CR; 2 PR; Table) and 6 had SD, for a disease control rate (DCR; CR+PR+SD) of 100%. Median treatment-free interval was 7.7 mo (IQR, 3.6-16.5); median duration of retreatment was 11.4 mo (IQR, 7.6-12.0). Seven pts (64%) were alive at cutoff. At data cutoff for KEYNOTE-052 (Sep 26, 2020), 10 pts were retreated; 5 (50%) had objective response to retreatment (1 CR; 4 PR) and 4 had SD, for a DCR of 90%. Retreatment BOR was PD for 1 pt (10%). Median treatment-free interval was 13.0 mo (9.2-16.6); median duration of retreatment was 6.0 mo (IQR, 4.9-9.2). Four pts (40%) were alive at cutoff. Conclusions: Although the number of pts who received retreatment was small, objective responses were observed. The findings are generally consistent with observations from retreatment in other tumor types (e.g., melanoma). Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]

Abstract P2-13-35: Pyrotinib combined with fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer: A single-arm phase II clinical trial

Abstract Background: HR+/HER2+ breast cancer is a unique molecular subtype of HER2+ breast cancer, which is characterized by mild biological behavior and is sensitive to endocrine therapy. Although the standard treatment for HR+/HER2+ metastatic breast cancer is chemotherapy combined with anti-HER2 therapy, this combination is not ideal for patients because of the heavy side effects of chemotherapy. Previous studies have shown that endocrine therapy combined with anti-HER2 therapy can also bring survival benefits to these patients. However, due to the limitations of previous treatment, the optimal combination mode of endocrine and anti-HER2 therapies has not been found. Pyrotinib is the most efficient pan-HER tyrosine kinase inhibitor (TKI) with irreversible blocking of HER2, while fulvestrant is the most potent estrogen receptor (ER) inhibitor. Previous cell experiments showed the cross-talk between ER and HER2 receptor pathways, indicating that the two signal pathways were important mechanisms of drug resistance for each other. Further research showed that ER inhibitor fulvestrant had synergistic effect with HER2 inhibitor pyrotinib. Therefore, we firstly explored the efficacy and safety of pyrotinib combined with fulvestrant in the treatment of HR+/HER2+ metastatic breast cancer.Methods: Eligible patients had histologically confirmed HR+/HER2+ metastatic breast cancer with no more than one line of prior treatment for metastatic disease. Those with central nervous system metastases or any prior HER2 TKI were excluded. Patients were treated with oral pyrotinib 400 mg once daily plus intramuscular injection of fulvestrant 500 mg on days 1, 15, and 29, and once every 28 days thereafter. The primary endpoint was progression-free survival (PFS), as assessed by the data and safety monitoring committee. Secondary endpoints included objective response rate, disease control rate (DCR), overall survival and safety. We also explored the efficacy of subgroups defined by different gene signatures, which were identified using comprehensive genomic variation profiling (FoundationOne CDx). This study is registered with ClinicalTrials.gov, NCT04034589.Results: From July 9, 2019 to June 20, 2021, 34 patients were enrolled; 19 (55.8%) patients had visceral metastases. Of 14 patients with measurable disease according to RECIST 1.1, seven (50%) achieved objective response. The DCR was 84.6%. Nine of the 34 included patients discontinued treatment because of disease progression, and PFS was immature. Twelve patients had available data of comprehensive genomic variation profiling, and the results showed that six patients had PIK3CA mutation, ten had TP53 mutation, and 11 had ErbB2 overexpression. The most common treatment-related adverse events were diarrhea and fatigue. The incidence of grade 3 or greater diarrhea was 12.1% (4/33) in patients with available safety data. No patient discontinued treatment because of adverse events. Conclusions: The combination of pyrotinib and fulvestrant was convenient and effective with manageable toxicity, which may offer a chemotherapy-free alternative treatment option for patients with HR+/HER2+ metastatic breast cancer. Citation Format: Ying Wang, Jianli Zhao, Zhongyu Yuan, Guorong Zou, Haiyan Li, Linxiaoxiao Ding, Yaping Yang, Jie Chai, Donggeng Liu, Herui Yao. Pyrotinib combined with fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer: A single-arm phase II clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-35.

Number needed to treat (NNT) analysis of patients in CheckMate 649 (CM 649): Nivolumab plus chemotherapy versus chemotherapy as first-line (1L) treatment for advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJ/EAC).

307 Background: Globally, GC/GEJ/EAC are one of the leading causes of cancer-related mortality. Systemic chemotherapy is the standard of care for advanced or metastatic GC/GEJC/EAC, but the prognosis is poor. In the CM 649 trial, nivolumab plus chemotherapy (Nivo+Chemo) demonstrated superior overall survival (OS) in patients with advanced GC/GEJC/EAC versus chemotherapy (Chemo) alone. The objective of this study is to estimate the NNTs comparing Nivo+Chemo versus Chemo for OS, progression free survival (PFS), and objective response rate (ORR) among patients in CM 649. Methods: Individual patient-level data from CM 649 were used for this analysis. The trial population included adult patients with previously untreated, unresectable, advanced or metastatic GC/GEJC/EAC who received Nivo+Chemo or Chemo alone as their 1L treatment. The analysis was performed in all randomized patients who received at least one dose of the study drug and a subgroup of patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Chemo included either FOLFOX (fluorouracil, oxaliplatin, and leucovorin) or XELOX (capecitabine and oxaliplatin). NNTs were equal to the reciprocal of the absolute risk reduction and were calculated for OS and PFS over the 1-year period and objective response rate (ORR) over the entire trial period. Results: 1,549 patients who received treatment in the CM 649 trial (782 treated with Nivo+Chemo and 767 treated with Chemo) were included in this analysis. Among these 1,549 patients, 933 patients had PD-L1 CPS ≥ 5 (468 treated with Nivo+Chemo and 465 treated with Chemo). Among all treated patients, the NNTs (95% confidence interval (CI)) of Nivo+Chemo when compared to chemotherapy were 14.08 (8.31–45.97) and 9.70 (6.59–18.36) for OS and PFS over the 1-year period, and 8.95 (5.95–18.10) for ORR over the entire trial period. Among patients with PD-L1 CPS ≥ 5, the NNTs (95% CI) were 9.06 (5.76–21.20) for OS, 6.91 (4.85–12.03) for PFS, and 7.14 (4.75–14.37) for ORR. This analysis shows that for every 100 patients with GC/GEJC/EAC receiving Nivo+Chemo instead of Chemo, there were 7 additional overall survivors (100/NNT of OS) and 10 additional progression-free survivors (100/NNT of PFS) in the 1-year period, and 11 additional patients achieving objective response (100/NNT of ORR) during the entire trial period. Among patients with PD-L1 CPS ≥ 5, there were 11 additional overall survivors and 14 additional progression-free survivors in the 1-year period, and 14 additional patients achieving objective response during the entire trial period. Conclusions: NNT analyses showed consistent and meaningful benefits of Nivo+Chemo over Chemo in terms of OS, PFS, and ORR. Nivo+Chemo represents a promising 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116.

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue "Diagnosis and Management of Endometrial Cancer".

Simple SummaryPatients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment with unsatisfactory clinical outcomes. The combination of carboplatin + paclitaxel is the standard first-line chemotherapy, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with mTOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high/mismatch repair (MMR)-deficient EC.Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

Hepatic Arterial Infusion Chemotherapy Followed by Lipiodol Infusion for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Single-Center Experience.

Background and Objectives: To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) followed by lipiodol infusion in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Materials and Methods: Thirty-two patients with advanced HCC and PVTT who received HAIC with regimens of cisplatin, mitomycin-C, and 5-fluorouracil followed by lipiodol infusion were enrolled. The primary efficacy endpoint was tumor response rate. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used for assessment of treatment response. The secondary endpoints were overall survival (OS) and progression free survival (PFS). Prognostic factors for survival also were evaluated. Results: The median OS and PFS were 11.9 and 9.5 months, respectively. Seventeen patients (53.1%) achieved objective response, and 23 patients (71.9%) achieved disease control. The length of survival in the responder and disease control groups was longer than in the non-responder and progressive disease groups after two cycles of HAIC (responder vs. non-responder: 16.5 vs. 7.9 months, p = 0.001; disease control vs. progressive disease: 12.3 vs. 5.6 months, p < 0.001) and after completing HAIC (responder vs. non-responder: 15.7 vs. 6.9 months, p = 0.001; disease control vs. progressive disease: 13.6 vs. 6.9 months, p < 0.001). Better survival was associated with Child-Pugh A liver function (p = 0.013), with early response to two HAIC cycles (p = 0.009), and with response (p = 0.02) and disease control (p = 0.001) after completing HAIC treatment. Conclusion: HAIC followed by lipiodol infusion is a safe and feasible treatment for advanced HCC with PVTT. Patients with early response could continue HAIC treatment with expected prolonged survival.

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study.

Chimeric antigen receptor (CAR) T-cell therapies that target either CD19 or CD22 alone have potent antilymphoma effects. However, antigen escape-mediated relapse often occurs. CAR T cells targeting both CD19 and CD22 may overcome this limitation. In this study, we developed bispecific CAR T cells simultaneously recognizing CD19- and CD22-expressing targets and assessed their safety and efficacy profiles in patients with relapsed/refractory aggressive B-cell lymphoma. Twenty-four patients were screened, and 16 were found eligible for the study. CAR T-cell-associated toxicities were recorded. Responses, overall survival (OS), and progression-free survival (PFS) were assessed. Of the 16 eligible patients, 14 (87.5%) achieved objective response and 10 (62.5%) achieved complete response (CR). The 2-year OS and PFS rates were 77.3% and 40.2%, respectively. Achieving CR (P = 0.046) and the number of prior chemotherapy lines (n = 2; P = 0.047) were independent prognostic factors associated with favorable PFS. The 2-year OS and PFS among patients who achieved CR were higher than among those who did not (P = 0.015 and P < 0.001, respectively). The 2-year PFS among patients who received two prior lines of chemotherapy was higher than that among patients who received more than two lines of chemotherapy (P = 0.049); OS did not differ between the groups. Severe grade 4 cytokine-release syndrome (CRS) was observed in 1 patient; 4 and 11 patients had grades 1 and 2 CRS, respectively. No patients developed neurotoxicity. CD19/CD22 dual-targeted CAR T cells may be a safe, potent antilymphoma cell-based targeted immunotherapy.

Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma

PurposeDespite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this...

Preliminary results of a phase I trial of FT516, an off-the-shelf natural killer (NK) cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line expressing high-affinity, non-cleavable CD16 (hnCD16), in patients (pts) with relapsed/refractory (R/R) B-cell lymphoma (BCL).

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received &gt; 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

PMC: A more precise classifier of POLE mutations to identify candidates for immune therapy.

3548 Background: Specific somatic mutations in DNA polymerase epsilon ( POLE) can cause a hypermutant phenotype with tumor mutation burden (TMB) in excess of 100 mutations per megabase. It has been reported that POLE mutant tumors are enriched in response to immune therapy and this association is being tested in multiple active clinical trials. However, most POLE mutations are passenger mutations and have no pathogenic role. Current methods to classify POLE mutations are limited in both accuracy and completeness, which could lead to inappropriate use of immune agents in tumor such as MSS CRC, where response rate is 5% or less. Here we present a new classifier, POLE Mutation Classifier or PMC, based on the unique trinucleotide mutation signature caused by selective loss of the proofreading function (LOP) of POLE. Methods: cBioPortal was queried to identify all tumors with POLE mutation. TMB was calculated for each, additionally, trinucleotide mutation signatures were obtained for all POLE mutant tumors in TCGA. Using OncoKB to identify a gold standard of 12 functional POLE mutations (n = 98 tumors) a POLE mutational signature was created. A combination of mutational signature, amino acid location, and TMB was used to classify each POLE variant. Results: Among all 48035 unique tumors the overall frequency of POLE mutations was 2.5% (n = 1184), however only 9.2% (n = 110) were determined to cause the selective LOP. The incidence of LOP POLE mutation was highest in uterine carcinoma and CRC, these tumors also had the highest ratio of LOP to passenger mutations. In a pan-cancer analysis the overall survival of LOP POLE patients was significantly better than those with passenger mutations (not-yet-reached vs. 51 mo, HR = 4.4, p &lt; 0.0001). A similar analysis performed using the polyphen-2 classifier to identify functional POLE mutations did not show a difference in overall survival (HR = 1.0, p-value = 0.57). To further validate the improved specificity of the PMC classifier TMB was used as a surrogate marker, using the PMC classifier 98% of tumors with LOP showed hypermutation (TMB &gt; 20mut/Mb), vs. 53% called functional by polyphen-2. A retrospective analysis of MD Anderson CRC patients identified 25 patients with LOP POLE mutation, who had improved OS relative to 267 CRC patients with passenger POLE mutation (not-yet-reached vs. 70 mo, HR:4.2, p = 0.028). Four metastatic CRC patients with LOP POLE mutation were treated with immune therapy (nivolumab, or ipilimumab/nivolumab) in 2nd or 3rd line, all four achieved objective response and remain on therapy (mean time on treatment 15 mo). Conclusions: The PMC classifier specifically identifies mutations in POLE that cause loss of the proofreading function, outperforming both manually curated databases and machine learning-based methods. Clinical trials that use POLE mutation as a selection criteria for immune therapy should be restricted to just those POLE mutations that cause LOP.

SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for advanced NSCLC with EGFR mutations: Data from a multicenter phase 1 study.

9055 Background: Despite the development of targeted therapies for advanced NSCLC harboring EGFR mutations ( EGFR+), acquired resistance remains inevitable. Immune checkpoint inhibitor as monotherapy has limited efficacy. Blockade of the TGF-β pathway which plays a key role in immune suppression may enhance the tumor response to anti-PD-1/PD-L1 antibodies. Here, we assessed SHR-1701, a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, in advanced NSCLC pts including one separate EGFR+ cohort. Methods: This phase 1 study includes a 3+3 dose-escalation and dose-expansion period of pretreated advanced NSCLC and multiple clinical expansion cohorts of different tumor types, genetic aberrations, or prior therapies. During the dose-escalation and dose-expansion period, pathologically confirmed pts received SHR-1701 at 3, 10, or 20 mg/kg Q3W or 20 mg/kg Q2W by intravenous infusion. The primary objectives were to determine the safety profile, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of SHR-1701. In the EGFR+ NSCLC clinical expansion cohort, histologically or cytologically confirmed advanced pts after at least 1L standard EGFR TKI received SHR-1701 at RP2D, and the primary endpoint was objective response rate (ORR). Treatment beyond progression was allowed. Results: During the dose-escalation and dose-expansion period, 30 pts were recruited: all stage IV; 83.3% had ≥2 metastasis sites; 76.7% had received ≥2L prior systemic therapy. One dose-limiting toxicity (immune-mediated pneumonitis) in the 20 mg/kg Q2W group was observed, and the MTD was not reached. Population pharmacokinetics and exposure‐response analysis of SHR-1701 based on this study and another phase 1 study for advanced solid tumors (NCT03710265) demonstrated 30 mg/kg Q3W as the RP2D. In the EGFR+ NSCLC cohort, 27 pts were enrolled: all stage IV; 77.8% had ≥2 metastasis sites; 70.4% had received ≥2L prior systemic therapy; 29.6% had 19-Del, 14.8% 19-Del and T790M, 7.4% 20-ins, 29.6% L858R, 18.5% L858R and T790M. With a median SHR-1701 exposure of 8.7 weeks (range, 3.0-24.0), 4 of the 24 pts who had at least one post-baseline radiographic assessment achieved objective responses, including 3 ongoing confirmed and 1 unconfirmed partial response. ORR was 16.7% (95% CI, 4.7%-37.4%), and disease control rate was 50.0% (95% CI, 29.1%-70.9%). Grade 3 treatment-related adverse events (TRAEs) occurred in 2 (7.4%) pts, including anemia, hypokalemia, and asthenia (1 [3.7%] for each). There were no grade 4 or 5 TRAEs. No pts discontinued treatment due to TRAEs. Conclusions: SHR-1701 monotherapy shows a manageable safety profile and encouraging antitumor activity in advanced EGFR+ NSCLC pts after failure of at least 1L standard EGFR TKI. Further investigation of SHR-1701 combination therapy for EGFR+ NSCLC is warranted. Clinical trial information: NCT03774979.

Pooled analysis of clinical activity of immune checkpoint immunotherapy in relapsing/refractory ES-SCLC.

e20572 Background: ES-SCLC is an aggressive lung cancer with high rates of relapse following induction regimens. Immune checkpoint immunotherapy (ICI) seems promising in the refractory/relapsing setting based on a smaller number of studies with smaller sample sizes. Here we report a pooled estimate of clinical activity of ICI in above patients based on published phase II/III trials so far. Methods: PubMed, EMBASE, Cochrane review, and clinicaltrials.gov databases were searched for phase II/III randomized controlled trials studying immune checkpoint immunotherapy in second or third line setting for ES-SCLC treatment. Data were extracted based on Reviews and Meta- Analysis guidelines. DerSimonian-Laird (DL) random effects model was used to estimate the pooled proportion of patients achieving objective response rate (ORR), pooled proportion of patients experiencing therapy related adverse events (TRAEs grade ≥ 1), pooled median progression free survival (PFS) and pooled median overall survival (OS), and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Outcomes were calculated by using ‘Metafor’ and ‘Meta’ packages by R-Studio and “CRAN” project. Results: Five studies with a total of 698 patients who received immune checkpoint immunotherapy were analyzed. Median age of patients who received treatment was 63 yrs. The pooled proportion of patients who achieved ORR was 15% (95% CI 0.11 to 0.20). Pooled Median PFS was about 1.54 (95% CI, 1.34- 1.74) months and median OS was 6.46 (95% CI, 5.13- 7.73) months. The pooled proportion of patients who experienced adverse events during the treatment was 49% (95% CI 0.38 to 0.60). Conclusions: ICI as second or third line treatment choice offers modest improvement in progression free survival and overall survival in ES-SCLC patients who have not received ICI as first line in combination with etoposide and platinum based therapies.