Median Progression-free Survival For Patients Research Articles

A Phase Ib Study of Linperlisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

▪IntroductionPeripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, where treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. PI3K inhibitors, blocking tumor cell proliferation, survival, migration, and modulating multiple functions on the tumor microenvironment have previously shown to be active in T cell lymphomas, as well as B-cell lymphomas and chronic lymphocytic leukemia. However, the use of these agents has been hampered by tolerability issues, including toxicities such as diarrhea, colitis, hepatotoxicity, pneumonitis, hyperglycemia, and rash. The PI3Kδ selective inhibitor, linperlisib, is a structurally novel oral agent that has been demonstrated to be clinically efficacious with a favorable safety profile in Phase 1 and Phase 2 trials in B-cell malignancies previously. Here we report updated clinical data with longer follow-up from a Phase 1b clinical trial of linperlisib monotherapy in relapsed or refractory PTCL.MethodsThe Phase 1b PTCL clinical trial (NCT04108325) was conducted at 10 sites in China. There were 43 patients (pts) with different PTCL histologies enrolled in the study, including PTCL-NOS (17 pts), AITL (16 pts), ALCL (6 pts), NKT (3 pts), and MEITL (1 pt). Tumor assessments are performed every two treatment cycles with 28 days as one treatment cycle using IWG 2007 criteria. Safety was evaluated according to CTCAE v5.0. Linperlisib was dosed at 80 mg QD (RP2D) orally until disease progression, intolerable toxicity or withdrawal from the study.ResultsIn the Phase 1b study of linperlisib monotherapy in r/r PTCL, as of a date cut-off of July 22, 2021, there were 43 pts enrolled with a median age of 58 years, ECOG 0-1 (41 pts, 95.3%), Stage III or IV (39 pts, 90.7%). The pts had a median of 2 prior systemic therapies, and 36 pts (83.7%) were refractory to their last treatment. The majority (83.7%) of pts had prior CHOP or CHOP-like therapy.Thirty-eight out of 43 pts (88.4%) experienced a treatment related adverse event (TRAE), majority (90.3%) of AEs were Grade 1 or Grade 2. The most common TRAEs (≥10%) were neutropenia (60.5%), leukopenia (37.2%), hypertriglyceridemia (37.2%), hypercholesterolemia (32.6%), AST increase (20.9%), ALT increase (23.3%), pneumonia (16.3%), anemia (16.3%), gamma glutamyl transpeptidase increase (16.3%), thrombocytopenia (14.0%), alkaline phosphatase increase (14.0%) and lymphocyte count increase (11.6%). The observed safety profile of linperlisib in r/r PTCL is similar to that observed in r/r follicular lymphoma, with no new toxicities reported. The Grade 3 and above AE occurring in >5% of pts was neutropenia (16.3%). Three pts had dose reductions to 60 mg QD due to AEs, and 5 pts discontinued from the study due to an SAE.Forty-one pts were evaluable for efficacy, 1 pt discontinued from study due to SAE occurred at C1D12, 1 pt discontinued from the study due to withdrawing consent at C1D12, there were no post baseline imaging assessment for these patients. The overall response rate (ORR) was 61.0%, including 34.1% Complete Response (CR), 26.8% Partial Response (PR) and 26.8% Stable Disease, contributing to a 90.0% Disease Control Rate (DCR). CR and/or PR were observed in all PTCL histologies enrolled in this study. Nearly all responses occurred by the first assessment at day 58. AS of a data cut-off of July 22，2021, the median PFS was 10.3 months (95%CI: 4.4-NR) , and the duration of response was not reached (95%CI: 8.5-NR). As of a data cut-off of July 22, 2021, 17 pts still remain on the study treatment, 7 pts had received at least 10 months of linperlisib treatment. Discontinuations were most frequently due to disease progression (18, 41.9%), intolerable SAE (5, 11.6%), or withdrawal consent from the study (3, 7.0%).ConclusionsThe PI3Kd-selective oral agent, linperlisib, demonstrated promising efficacy and durable responses with a 61.0% ORR and 10.3 months median PFS in patients with r/r PTCL. Additional clinical studies of linperlisib in r/r PTCL, including a Phase 2 registration study, are currently ongoing. DisclosuresNo relevant conflicts of interest to declare.

Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma

BackgroundThe identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC.MethodsWe performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients.ResultsA total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with <mNER compared to 21.8% among patients with >mNER (OR 2.39, p = 0.04). The median PFS for patients with <mNER was significantly longer at 8.6 months (mo) compared to 3.2 mo for patients with >mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with <mNER compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with <mNLR showed improvement in OS (HR 0.42, p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group.ConclusionsA lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

Efficacy and Safety of Anlotinib Monotherapy as Third-Line Therapy for Elderly Patients with Non-Small Cell Lung Cancer: A Real-World Exploratory Study

PurposeThe present study was to investigate the real-world efficacy and safety of anlotinib monotherapy as third-line therapy for elderly patients with advanced non-small cell lung cancer (NSCLC).MethodsA total of 83 elderly patients (>65 years) with NSCLC who were progressed at least two lines of previous systemic therapy were recruited retrospectively. Patients were treated with anlotinib monotherapy (12 mg or 10 mg). Efficacy of anlotinib was assessed and all the patients were followed up regularly. Adverse reactions were collected during anlotinib administration. Univariate analysis was performed using Log rank test and multivariate analysis was adjusted by Cox regression analysis. Additionally, prognostic analysis according to common adverse reactions was implemented to identify the potential clinical significance.ResultsThe best overall response of the 83 elderly patients during anlotinib monotherapy indicated that partial response (PR) was observed in six patients, stable disease (SD) was noted in 59 patients, and progressive disease (PD) was reported in 18 patients. Consequently, the objective response rate (ORR) was 7.2% (95% CI=2.7–15.1%) and the disease control rate (DCR) was 78.3% (95% CI=67.9–86.6%). The median progression-free survival (PFS) of the 83 elderly patients with NSCLC was 4.2 months (95% CI=3.51–4.89). Furthermore, the median overall survival (OS) of the 83 patients was 9.6 months (95% CI=6.65–12.55). The safety profile suggested that the relatively common adverse reactions of the elderly patients with ES-SCLC receiving anlotinib therapy were hypertension (49.4%), fatigue (45.8%), and hand–foot syndrome (39.8%). Interestingly, association analysis exhibited that the median PFS of patients with hypertension and non-hypertension was 4.5 and 3.0 months, respectively (χ2=6.306, P=0.012).ConclusionAnlotinib monotherapy demonstrated a satisfactory efficacy and tolerable safety profile in third-line settings for elderly patients with advanced NSCLC. Patients who experienced a hypertension adverse reaction induced by anlotinib therapy might confer superior PFS. The conclusion should be validated in prospective clinical trials subsequently.

Retrospective Chart Review of Dabrafenib Plus Trametinib in Patients with Metastatic BRAF V600-Mutant Melanoma Treated in the Individual Patient Program (DESCRIBE Italy).

BackgroundReal-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy).ObjectiveTo describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy.Patients and methodsAn observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated.ResultsOverall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5–67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6–10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram.ConclusionTreatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden – concordant with the results of the pivotal phase 3 studies of dab + tram.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00850-1.

Cytoreductive Surgery versus Systemic Chemotherapy alone in Isolated Peritoneal Carcinomatosis of Colorectal Origin.

To compare the overall survival and progression-free survival of front-line cytoreductive surgery (CRs) ± hyperthermic intraperitoneal chemotherapy versus intensive systemic chemotherapy alone, in patients with isolated peritoneal carcinomatosis of colorectal origin. Descriptive study. Departments of Medical Oncology and Surgical Oncology in University of Health Sciences, Umraniye Education and Research Hospital, from January 2017 to January 2020. Clinicopathological data of patients presented with isolated peritoneal carcinomatosis were categorised into two groups according to their treatment type as patients who received intensive systemic chemotherapy alone or underwent front-line CRS ± HIPEC. Overall and progression-free survival outcomes of the two approaches were quantified by survival analysis and compared with each other. The other collected variables were age, gender, performance status, tumor site and type of systemic chemotherapy. Overall, 109 patients were included. The median progression-free survival of patients treated with cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy was 12 months; whereas, it was 9 months in those treated with intensive systemic chemotherapy alone (p=0.011). The median overall survival was estimated as 32 months in patients treated with cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy, compared with 23 months for those treated with systemic chemotherapy alone (p=0.715). Although not translated into overall survival gain, extended progression-free survival, may give an advantage to cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy when used with intensive systemic chemotherapy in the individualised treatment of isolated peritoneal carcinomatosis of colorectal carcinoma. Key Words: Colorectal carcinoma, Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy, Overall survival, Peritoneal carcinomatosis, Systemic chemotherapy.

Role of integrins in the metastatic spread of high-grade serous ovarian cancer

PurposeIntegrins may be involved in the metastatic spread of high-grade serous ovarian cancer (HGSOC) which determines the therapeutical approach and prognosis. We investigated the integrin expression in primary tumor and metastases of advanced HGSOC.MethodsThe expression of integrin α2, α4, α5, α6, and β1 was assessed by immunostaining in tumor samples of the ovary, omentum, and peritoneum of each patient. Differences in integrin expression among tumor localizations and their association with clinicopathological parameters were examined by Fisher’s exact test. The impact of integrin expression on progression-free survival (PFS) and overall survival (OS) was examined by Cox regression and Kaplan–Meier analyses.ResultsHundred and thirteen tumor samples of 40 HGSOC patients were examined. The expression of the integrins did not differ between the three tumor localizations (all p values > 0.05) with the exception of high expression of integrin α4 in primary tumor and omentum (52.5% versus 47.5%, p = 0.008) and primary tumor and peritoneum (52.5% versus 47.5%, p = 0.050). High expression of integrin α4 in peritoneum was associated with poorer PFS (HR 2.02 95% CI 1.01–4.05, p = 0.047), younger age (p = 0.047), and death (p = 0.046). Median PFS in patients with high expression of integrin α4 was 13.00 months, whereas median PFS in patients without high expression of integrin α4 was 21.00 months (p = 0.040). Expression of other integrins did not correlate with PFS or OS.ConclusionExpression of integrin α4 may be altered during the metastatic spread of HGSOC and affect prognosis, whereas expression of integrin α2, α5, α6, and β1 did not reveal any prognostic value.

Cabozantinib in the treatment of metastatic renal cell carcinoma - final data analysis from four oncology centers in the Czech Republic.

Current standard treatments for patients with metastatic renal cell carcinoma (mRCC) involve tyrosine kinase inhibitors (TKI) that inhibit angiogenesis. Cabozantinib is a multi TKI used for the treatment of mRCC in the first- and second-line setting. The aim of this study was the final analysis of treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib after previous targeted therapy. A total of 54 patients with mRCC from four oncology centers in the Czech Republic were evaluated retrospectively; the median follow-up was 18.5 months. Cabozantinib was administered in a dose of 60mg/day, a subset of patients received an initial dose of 40mg/day. The treatment was administered until the progression. The Kaplan-Meier analysis was used to calculate progression free survival (PFS) and overall survival (OS). We performed a multivariate analysis of risk factors for treatment outcomes (PFS, OS) by regression analysis. All statistics were evaluated at the significance level &#945; = 0.05. The median PFS in all patients was 9.3 months (95% CI 7.2 - 11.4). The median OS in all patients was 21.9 months (95% CI 15.5 - 28.4). The median PFS in patients with bone metastases was not statistically significantly different compared with patients without bone metastases (9.3 vs 8.7 months, P = 0.53). The median OS in patients with bone metastases was statistically significantly shorter compared with patients without bone metastases (17.7 vs 26.8 months, P = 0.021). A treatment response was observed in 40.7 % of cases, including one complete remission. The regression analysis demonstrated a significant effect on OS in patients with the presence of subsequent treatment (P = 0.001), patients with treatment duration of first line therapy 6 months (P = 0.019) and 12 months (P = 0.003) and in patients without bone metastases (P = 0.021). Our final analysis of patients with mRCC treated with cabozantinib after previous targeted therapy confirmed its effectiveness.

18F-FDG-PET/CT as an imaging biomarker for regorafenib efficacy in metastatic colorectal cancer (JACCRO CC-12).

IntroductionRegorafenib is a multikinase inhibitor approved for the treatment of metastatic colorectal cancer (mCRC). Despite providing a statistically significant survival benefit, a substantial number of patients fail to respond to or continue with treatment, which has resulted in an unmet clinical need for a biomarker of regorafenib efficacy.MethodsThe JACCRO CC-12 study was a prospective, multicenter, single-arm phase II trial designed to evaluate the usefulness of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) as an imaging biomarker of regorafenib in patients with mCRC that progressed after standard chemotherapies. FDG-PET and contrast-enhanced computed tomography (CT) were performed before and after treatment with regorafenib 160 mg once daily 3 weeks on/1 week off. The primary end point was the change in the maximum standardized uptake value in the lesion with the highest uptake at pre-treatment FDG-PET. The secondary end points included overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), safety, and the correlation between FDG-PET and CT.ResultsTwenty patients were enrolled from November 2014 to March 2016, 17 of whom were evaluated for metabolic and morphological changes. Metabolic response with FDG-PET was partial response (PR) in one case (5.9%), stable disease (SD) in four (23.5%), and progressive disease (PD) in 12 (70.6%). The metabolic response rate was 5.9%. On CT imaging, no complete response or PR was observed, and the ORR was 0%. Median PFS and OS were 1.7 and 9.8 months, respectively. The median PFS of patients who achieved PR or SD by FDG-PET was 3.7 months, whereas that of those assessed as PD was 1 month (p = 0.13). The median OS of patients who achieved PR or SD by FDG-PET was 13.0 months, whereas that of patients assessed as PD was 10.6 months (p = 0.43). Frequent adverse events were palmar–plantar erythrodysesthesia syndrome, hypertension, loss of appetite, and fatigue.ConclusionsIn this study, FDG-PET failed to demonstrate usefulness as an early imaging biomarker of regorafenib in patients with mCRC.

Clinical outcomes of patients taking first-generation EGFR-TKIs may predict the benefits afforded by osimertinib in EGFR T790M-mutant NSCLC patients.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used to treat patients with EGFR-mutated non-small cell lung cancers (NSCLCs). The association between the clinical outcomes of patients on first-line EGFR-TKIs and the efficacy of osimertinib as second-line treatment has not been previously assessed. This is our topic here. We retrospectively analysed 67 patients with EGFR mutations on osimertinib after treatment with first-generation EGFR-TKIs. We evaluated patient characteristics, the EGFR T790M allele frequency in plasma samples and clinical outcomes. When osimertinib was given as second-line treatment, the median progression-free survival (PFS) was 6.0months, and the response rate and disease control rate were 32.8% and 91.0%, respectively. Correlation analysis showed that the female sex and isolated (not multiple) progression on first-line EGFR-TKIs were correlated with a superior response to osimertinib. Kaplan-Meier analysis showed that patients exhibiting a partial response, isolated progression, and longer PFS on first-line EGFR-TKIs experienced prolonged PFS on osimertinib. Univariate analysis indicated that the treatment response, PFS and progression when on first-line EGFR-TKIs affected the PFS on osimertinib. Multivariate analysis showed that progression when on first-line EGFR-TKIs was independently prognostic of a response to osimertinib. The median PFS of patients with isolated progressive disease PD alone who were receiving brain radiotherapy was significantly longer than that of patients with isolated progressive disease alone who did not receive brain radiotherapy as well as patients exhibiting multiple progression. A low frequency of the EGFR T790M allele in plasma tended to predict an inferior efficacy of osimertinib and shorter PFS. We found that patients who benefited from first-line EGFR-TKIs may experience prolonged PFS and a higher response rate when subsequently given osimertinib. A low plasma frequency of the EGFR T790M allele may predict poor osimertinib efficacy and shorter PFS.

Adverse Events as a Potential Clinical Marker of Antitumor Efficacy in Ovarian Cancer Patients Treated With Poly ADP-Ribose Polymerase Inhibitor.

BackgroundPARP inhibitor (PARPi) is an important progress in ovarian cancer treatment. The available evidence suggests that BRCA mutation and homologous recombination deficiency (HRD) are effective biological markers for PARPi. Here we investigated the relationship between adverse events (AEs) and efficacy of PARPi in ovarian cancer patients.MethodsSeventy-eight patients with ovarian cancer patients underwent Olaparib and Niraparib from July 2018 to July 2020 were analyzed. AEs were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Chi-square test or fisher exact tests was performed to observe the association between categorical variables. Logistic regression analysis was conducted to investigate the independent variables for disease control response (DCR). Progression-free survival (PFS) was compared between AEs variables by log-rank test.ResultsPatients with AEs in the first one week had a higher DCR compared with those after one week (86.11% versus 60.98%, p=0.013). Patients with serious AEs (SAEs) had a significantly higher DCR (81.40% versus 60.60%, p=0.045). There were associations between anemia and DCR in both occurrence (79.63% versus 56.52%, p=0.037) and grade (100% versus 73.17%, p=0.048). The median PFS of patients with hematological toxicity was longer than that of patients with no-hematological toxicity (30 versus 20 weeks, p=0.047). Patients with hematological toxicity within four weeks had prolonged median PFS than those with hematological toxicity after four weeks (40 versus 22 weeks, p=0.003).ConclusionsThe early presence of AEs and SAEs in hematological toxicity of PARPi were related to the antitumor efficacy, which might be a valid and easily measurable clinical marker in ovarian cancer patients.

Efficacy and Safety of Regorafenib Monotherapy among Patients with Previously Treated Metastatic Colorectal Cancer in a Chinese Population: A Real-World Exploratory Study.

BackgroundPresent study was condeucted to investigate the efficacy and safety of regorafenib for patients with previously treated metastatic colorectal cancer (mCRC) in a Chinese population and the prognostic implications of adverse reactions.MethodsThis retrospective study a total of 96 consecutive patients with mCRC who had failed standard chemotherapy regimens from June 2017 to December 2020. Patients received regorafenib at an initial dosage of 160 mg or 120 mg. The primary end point was progression-free survival (PFS), and secondary end points objective response rate (ORR), disease-control rate (DCR), overall survival (OS), safety, and associations between prognosis and adverse-reaction status.ResultsThere were three patients with partial response, 49 with stable disease, and 44 with progressive disease. Consequently, the ORR and DCR of the 96 patients were 3.1% (95% CI 0.6%–8.9%) and 54.2% (95% CI 43.7–64.4%), respectively. Prognosis results showed that median PFS of the 96 patients was 2.5 (95% CI 1.98–3.02) months and median OS 9.8 (95% CI 7.02–12.59) months. Additionally, the most frequent adverse reactions during regorafenib treatment were hand–foot syndrome (HFS; 52.1%), hypertension (38.5%), and fatigue (33.3%). Interestingly, the relevance of prognosis to adverse-reaction status exhibited that median PFS of patients with HFS and patients without HFS was 3.3 months and 2.0 months, respectively (P=0.013). Similarly, median PFS of patients with hypertension and without hypertension was 3.6 months and 2.2 months, respectively (P=0.023).ConclusionPotential clinical benefit of regorafenib monotherapy was observed for patients with mCRC who had failed standard chemotherapy regimens. Hypertension and HFS induced by regorafenib therapy could be used as valuable biomarkers to predict the prognosis of regorafenib.

P16-3 Maintenance therapy in HER2 and hormone receptor-positive breast cancer

After the standard first-line treatment for HER2 and hormone receptor-positive breast cancer, maintenance therapies are still controversial. Here, we report the real-world data of trastuzumab plus endocrine therapy compared with trastuzumab plus chemotherapy in HER2 and hormone receptor-positive metastatic breast cancer. This retrospective, multicenter, observational cohort study enrolled women aged 18 years or older with measurable or evaluable HER2 and hormone receptor-positive metastatic breast cancer who received chemotherapy and trastuzumab as first-line treatment between January 2009 and October 2019. We evaluated the efficacy and safety of trastuzumab plus endocrine therapy and trastuzumab plus chemotherapy. 102 patients were selected: 67 (65.7%) patients received trastuzumab plus endocrine therapy including aromatase inhibitors, fulvestrant, tamoxifen, or toremifene. While 35 (34.3%) patients received trastuzumab plus chemotherapy including capecitabine or vinorelbine as maintenance therapy. Maintenance endocrine therapy significantly improved progression-free survival (PFS) compared with chemotherapy (median progression-free survival 10.6 months [95% CI 8.609-12.658] vs 6.7 months [5.276-8.058], respectively; adjusted hazard ratio [HR] 0.648 [95% CI 0.428-0.981], p=0.040). The median PFS in patients without brain metastasis was 10.8 months (95% CI 9.380-12.154) in the endocrine therapy group versus 6.7 months (5.202-8.132) in the chemotherapy group (HR 0.485 [95% CI 0.303-0.777]), p=0.003). The most common adverse event was arthralgia (8,12%) in the endocrine therapy group, while hand-foot syndrome (25,71%) occurred in the chemotherapy group. Maintenance endocrine therapy could improve the survival of HER2 and hormone receptor-positive metastatic breast cancer patients.

Abstract 984: Targeting BCL-xL addiction with APG-1252 (pelcitoclax) to overcome apoptotic blockade in neuroendocrine neoplasm (NEN)

Abstract Current targeted therapies such as VEGFR inhibitor sunitinib and mTOR inhibitor everolimus extend progression-free survival (PFS) in patients with Grade 1 (G1) and G2 neuroendocrine tumors (NET), but the objective response rate remains low. The median PFS in patients with advanced neuroendocrine carcinoma (NEC) receiving platinum-based therapy is only 3 to 4 months. Hence, more effective therapy is needed to improve clinical outcomes. This study explored if BCL-2 family antideath proteins play a role in NEN tumorigenesis and whether clinical-stage dual BCL-2/BCL-xL inhibitor APG-1252 might overcome intrinsic apoptotic blockade in NEN. A panel of six NEN cell lines were exposed to APG-1252-M1, which is an active metabolite of APG-1252 typically used for in vitro studies. After 72 hours, the IC50 of APG-1252-M1 ranged from 0.43 to 10 μM. Among the panel, pancreatic NET (pNET) cell lines BON-1 and β-TC3 exhibited the highest sensitivity, with IC50 values of 0.43 and 0.55 µM, respectively, whereas NEC cell line NCI-H460 was insensitive to APG-1252-M1. Interestingly, Western blot analysis revealed higher expression of BCL-xL compared to BCL-2 and MCL-1 proteins in NET cell lines (BON-1, QGP-1, NCI-H727). Higher baseline levels of BCL-xL:BIM and BCL-xL:PUMA complexes in NEN cells indicated APG-1252-M1 sensitivity. Exposure to APG-1252-M1 disrupted these complexes, liberating BIM/PUMA to trigger the apoptotic cascade, as indicated by an increase in BAX:BAK complexes. Conversely, lower BCL-xL complex levels and higher MCL-1 levels correlated with insensitivity of NCI-H460 to APG-1252-M1. Immunohistochemistry staining of BCL-xL, BCL-2, and MCL-1 proteins was performed in formalin-fixed paraffin-embedded tissue sections of 106 NEN patient tumors (including stomach/intestine/pancreatic NEN), of which approximately 70% were NET and 30% NEC. Similar to data in NEN cell lines, BCL-xL expression was higher than BCL-2 expression in NEN patient samples, in which BCL-xL expression was indicated by more than 80% of samples with IHC scoring ≥6 on a scale of 0 to 10, and BCL-2 expression by 30% IHC scoring &amp;lt; 6 or undetectable (60% IHC scoring 0). Unexpectedly, however, MCL-1 expression was also high, with more than 80% of samples IHC scoring ≥6. In summary, the results suggest that BCL-xL plays an important role in NEN. Cellular sensitivity to BCL-2/BCL-xL inhibitor APG-1252-M1 correlates with baseline BCL-xL complex levels. In NEN patient samples, MCL-1 was also highly expressed, implicating its potential negative regulatory effect on sensitivity to APG-1252. Concurrent expression of BCL-xL and MCL-1 proteins suggests that a combination treatment targeting both proteins might be more effective in NEN. Our findings inform development of a BCL-2/BCL-xL inhibitor for NEN therapy. Citation Format: Yu Guo, Jing Deng, Lin Zhang, Xiaojing Huang, Kaixiang Zhang, Feng Zhou, Yuanbao Li, Fan Luo, Douglas D. Fang, Dajun Yang, Jie Chen, Yifan Zhai. Targeting BCL-xL addiction with APG-1252 (pelcitoclax) to overcome apoptotic blockade in neuroendocrine neoplasm (NEN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 984.

Relapsed or Refractory Multiple Myeloma Patients Treated with Second-Line Carfilzomib and Categorized By Prior Exposure to Bortezomib: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Relapsed or Refractory Multiple Myeloma Patients Treated with Second-Line Carfilzomib and Categorized By Prior Exposure to Bortezomib: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Prolonged Progression Free Survival and Time to Next Treatment Are Achievable Outcomes in Patients with Systemic AL Amyloidosis Treated with Novel Agent Chemotherapy: Analysis of the Alchemy Study

BackgroundSystemic AL amyloidosis (AL) is associated with an underlying plasma cell dyscrasia and caused by deposition of abnormally folded monoclonal immunoglobulin light chains. Novel chemotherapy has improved overall survival (OS) and haematological responses in recent years but little is known about durability of treatment response in this disease. In multiple myeloma, progression free survival (PFS) without ASCT is short. We report data on PFS and time to next treatment (TNT) in a predominantly non-ASCT population from the ALChemy study, a large prospective study of patients with AL.MethodsAll patients with newly diagnosed AL amyloidosis from January 2009 to March 2016 were included. All underwent serial organ function assessment, imaging and biomarkers. Organ involvement and responses were defined by international amyloidosis consensus criteria. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis (patients who died before response assessment were assessed as non-responders). Progression free survival (PFS) was defined as time to death or progression to next line of chemotherapy. Time to next treatment (TNT) was defined as time from the beginning of first line therapy to the next line.Results1203 patients were recruited. Median age was 66.3 years (29.5-89.4), M:F 58%:42%, median NT-proBNP was 1974ng/L and median dFLC was 181.7mg/L. 62 patients (5.2%) died before treatment initiation. Treatments were: bortezomib-based regimen (mainly CyBorD) - 57.6%, immunomodulatory (IMID)-based (mainly CTD) - 32.4%, oral melphalan-dexamethasone - 5%, rituximab-based regimen - 3.2%, upfront ASCT - 1.3%, other - 0.5%. Median number of chemotherapy cycles was 5. Overall haematological response (FLC and M-protein response) at 6 months on an ITT basis (n=1037) was: CR 17.6%, VGPR 15.3%, PR 17.7% and non-response 49.4%. On an evaluable basis, overall haematological response at 6 months (n=723) was: CR 25.3%, VGPR 22%, PR 27.1% and non-response 25.6%.260 patients (21.6%) died within 6 months of diagnosis. Median OS was 47 months. Median PFS and TNT of the whole cohort was 17 months and 54 months respectively (Fig 1a and 1b). Median TNT in Mayo Stage 1, 2, 3A and 3B was 44, 46, 48 months and not reached (no second line treatment by 5 years = 54%), (p=0.63). Median PFS in Mayo Stage 1, 2, 3A and 3B was 34, 26, 14 and 4 months respectively (p<0.001).Median OS was not reached in patients who achieved an overall PR, VGPR or CR at 6 months, compared to median OS of 8 months in non-responders (p<0.001). Median PFS in patients who achieved an overall CR, VGPR, PR or non response at 6 months was: not reached (5 year PFS = 77%), 54 months, 20 months and 5 months respectively (p<0.001) (Fig. 1c). Median TNT in patients in overall CR, VGPR, PR or non response at 6 months was as follows: not reached (66% at 5 yrs), not reached (55% at 5 yrs), 26 months and 15 months (p<0.001) (Fig. 1d).Median OS in patients treated with bortezomib, IMID and melphalan was: 83 months, 55 months and 42 months respectively (p=0.11). Median OS in Stage 3 patients treated with bortezomib and IMID was 38 and 12 months respectively (p=0.001). Median PFS in patients treated with bortezomib, IMID and melphalan was: 21, 15 and 14 months (p=0.04). Among patients with stage 3 disease, median PFS in patients treated with bortezomib and IMID was 15 and 7 months respectively (p<0.001). Median TNT in patients treated with bortezomib, IMID and melphalan was: not reached (no second line by 5 years = 57%), 32 and 26 months (p=0.001). Among Stage 3 patients, median TNT in patients treated with bortezomib and IMID therapy was not reached (no second line by 5 years = 63%) and 28 months respectively (p<0.001).ConclusionThese prospectively collected data from a real world setting report on progression free survival and time to next treatment in AL with predominant non-transplant novel agent based regimens, which has thus far been lacking. Patients treated with bortezomib based therapy had superior PFS, TNT and OS. Median TNT was 4.5 years. Strikingly, PFS and TNT were remarkably long in patients achieving a complete haematological response (PFS 77% at 5 years) - akin to those previously reported in patients treated with upfront ASCT and perhaps raising questions about the role of upfront ASCT. These data confirm the efficacy of bortezomib based regimens in AL amyloidosis and the value of CR as the goal of induction therapy in this disease. [Display omitted] DisclosuresWechalekar:Celgene: Honoraria; Janssen: Honoraria.

Miroir: A National, Multicenter, Non-Interventional Study of Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) Treated with Pomalidomide (POM) in France

BACKGROUNDPOM combined with low-dose dexamethasone (LoDEX) has demonstrated efficacy in patients with RRMM, with a median progression-free survival (PFS) of 4.0 months in a phase 3 study (MM-003; San Miguel, et al. Lancet Oncol . 2013;14:1055-1066). This trial led to the European approval of POM + LoDEX for RRMM previously treated with ≥ 2 regimens, including lenalidomide (LEN) and bortezomib. However, data from clinical practice on the use of POM are limited. Thus, the MIROIR study aims to describe the efficacy and tolerability of POM in current clinical practice in France.METHODSAdults (≥ 18 years of age) with multiple myeloma initiating POM treatment in France between October 1, 2014, and September 30, 2016, and previously included in the Imnovid (POM) registry were included in this interim analysis. Data were collected from patient medical records. The efficacy of POM was estimated by PFS (defined as the time between POM initiation and the first progression according to International Myeloma Working Group criteria or death) and by time to next treatment (TTNT; defined as the time between POM initiation and initiation of the next line of chemotherapy). The primary endpoint is PFS at 6 months. This study is still ongoing and recruiting patients and is registered at ClinicalTrials.gov: NCT02902900.RESULTSAs of September 30, 2016, a total of 1092 patients were enrolled from 123 centers. Demographic characteristics at POM initiation are provided in the Table. The median follow-up time was 10.1 months (95% CI, 9.7-10.6). The median PFS was 4.9 months (95% CI, 4.4-5.6), and the PFS rate at 6 months was 44.9% (95% CI, 41.8%-48.0%). The median TTNT was 11.0 months (95% CI, 9.5-11.9), and the proportion of patients with ongoing POM treatment at 6 months was 70.1% (95% CI, 66.9%-72.9%). The median PFS with POM in patients who had LEN (n = 512) or another treatment (n = 580) immediately before POM initiation was 4.7 months (95% CI, 4.0-5.5) and 5.2 months (95% CI, 4.3-6.1 ), respectively. The median PFS in patients receiving ≤ 2 (n = 366), 3 (n = 355), or ≥ 4 (n = 371) prior lines of therapy was 6.2 months (95% CI, 5.4-9.6), 4.0 months (95% CI, 3.4-5.2), and 4.4 months (95% CI, 3.7-5.1), respectively. In patients < 75 (n = 764) or ≥ 75 (n = 328) years of age, the median PFS was 5.4 months (95% CI, 4.7-6.1) and 4.0 months (95% CI, 3.4-4.9), respectively. In the full patient population, the median overall survival was 18.9 months (95% CI, 17.1-not reached), and the survival rate at 12 months was 63.4% (95% CI, 59.8%-66.8%). The most frequent serious adverse events related to POM (n = 167) were neutropenia (10.8%), thrombocytopenia (6.0%), and asthenia (5.4%). Adverse events led to POM dose reduction, temporary POM interruption, or definitive POM interruption in 19.9%, 29.6%, and 16.6% of patients, respectively. A total of 214 patients (19.6%) received erythropoietin concomitant to POM treatment. The numbers of patients who received prophylactic antithrombotic, antibiotic, and antiviral therapy were 872 (79.9%), 568 (52.0%), and 669 (61.3%), respectively.CONCLUSIONSThese interim efficacy and safety results on POM use in current practice in France confirm the promising results reported in the pivotal, phase 3 study of patients with RRMM treated with POM + LoDEX. Results were similar regardless of whether LEN or another treatment was used immediately before POM initiation. A centralized review of these preliminary PFS results will be performed to improve the robustness of these findings and to provide a better understanding of the clinical practice of POM use in patients with RRMM in France. [Display omitted] DisclosuresHulin:JANSSEN: Honoraria. Macro:JANSSEN: Honoraria. Gourgou:Roche: Other: expertise methodological seminar Force 1 since 2007 + real life study; Celgene: Other: expertise methodological mirror. Perrot:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Takeda: Honoraria. Karlin:Janssen: Honoraria, Other: Travel expenses. Fohrer:Celgene Corporation: Consultancy. Eveilard:Celgene Corporation: Consultancy. Decaux:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenstrom's Macroglobulinemia: Update of Pivotal Clinical Trial

MYD88 mutations are present in 95% of WM patients and trigger malignant cell growth through Bruton's Tyrosine Kinase and Hematopoietic Cell Kinase, both targets of ibrutinib. CXCR4 mutations are found in 30-40% of previously treated WM patients and confer in vitro resistance to ibrutinib. We therefore performed a prospective study that examined the activity of ibrutinib in previously treated WM patients (Treon et al, NEJM 2015). The findings showed that ibrutinib was highly active in previously treated WM patients and supported the first ever FDA and EMA drug approval for the treatment of WM. Herein, we provide a long-term follow-up of this study. Sixty-three symptomatic WM patients who received at least one prior therapy were enrolled. Their baseline characteristics were as follows: median age 63 (range 44-86 yrs); 48 (76%) were male, IPSSWM scores were low (n=14; 22%), intermediate (n=27; 43%), and high (n=22; 35%); median serum IgM was 3,520 (range 724-8,390 mg/dL); median hemoglobin level was 10.5 (range 8.2-13.8 g/dL); median serum B2M level was 3.9 (1.3-14.2 mg/L); adenopathy >1.5 cm (n=37; 59%); splenomegaly >15 cm (n=7; 11%), and median bone marrow disease involvement was 60% (range 3-95%). The median prior therapies was 2 (range 1-9), and 25 (40%) patients were refractory to their previous therapy. MYD88 and CXCR4 genotyping was performed for 63 and 62 patients, respectively and is shown in Table 1. Patients were initiated on 420 mg a day of ibrutinib, and dose de-escalation for toxicity was permitted. Patients received protocol administered ibrutinib for 40 months, and transitioned to commercial supply thereafter. Patients could consent to continue follow-up for response assessment after 40 months on commercial drug supply. Ibrutinib was administered until progression or intolerance. The median time on ibrutinib was 46.6 (range 0.5-60 months). Improvements in categorical responses occurred with prolonged treatment. The overall and major (>PR) response rates were 90.4% and 77.7%, respectively, and were not impacted by prior lines of therapy or relapsed or refractory status. Seventeen (27%) patients achieved a VGPR. No complete responses were observed. At best response, median serum IgM level declined from 3,520 to 821 mg/dL (p<0.0001). At baseline 46/63 (73%) patients had a serum IgM >3,000 mg/dL versus 4/63 (6%) patients at best response (p<0.0001). At best response, median bone marrow involvement declined from 60% to 20% (p<0.0001), and the median hemoglobin level increased from 10.5 to 14.2 g/dL (p<0.0001). The impact of MYD88 and CXCR4 mutation status on responses and time to at least a minor (overall) and PR or better (major) response are shown in Table 1.Figure 1 shows the Kaplan Meier curves for progression free survival (PFS) for all study participants (A), and those genotyped by MYD88 and CXCR4 mutation status (B). With a median study follow-up of 47.1 months, the median PFS for patients with MYD88MutCXCR4WT has not been reached. By comparison, the median PFS was 45 months for patients with MYD88MutCXCR4Mut, and 21 months for those with MYD88WTCXCR4WT (Log-rank p=0.0093 for 3-way comparison). Three patients died due to disease progression.Adverse events (Grade >2) that were at least possibly related to protocol therapy in >5% of patients during protocol therapy were as follows: anemia (n=4); atrial fibrillation (n=6); GERD (n=5); hypertension (n=5); neutropenia (n=14); pneumonia (n=6); skin infection (n=3); thrombocytopenia (n=9). Seven patients (11%) had atrial arrhythmia [Grade 1 (n=1); Grade 2 (n=5); Grade 3 (n=1)] on ibrutinib. Six of these patients continued ibrutinib with medical management for their atrial arrhythmia. Four patients came off protocol therapy for toxicity: atrial fibrillation (n=1); infection not related to drug therapy (n=1), procedure related hematoma (n=1), and thrombocytopenia (n=1). The findings from the long-term follow-up of this pivotal study confirm that ibrutinib is highly active in symptomatic patients with relapsed and refractory WM, and produces durable responses. Prolonged ibrutinib therapy is associated with improvements in categorical responses, including attainment of VGPR. Ibrutinib response activity and PFS are impacted by MYD88 and CXCR4 mutation status in this patient population. (ClinicalTrials.gov number, NCT01614821.) [Display omitted] DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Laubach:Novartis, Takeda, Celgene: Consultancy; Novartis, Takeda, Celgene, Onyx: Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding. Palomba:Merck: Consultancy. Advani:Pharmacyclics: Consultancy; Pharmacyclics: Research Funding; Janssen: Research Funding; Infinity: Research Funding; Juno Therapeutics: Consultancy; Agensys: Research Funding; Celgene: Research Funding; Nanostring: Consultancy; Cell Medica: Research Funding; Genentech: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Spectrum: Consultancy; Sutro: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Kura: Research Funding.

An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers.

Simple SummaryPARP inhibitors, a family of targeted cancer therapeutics, have been shown to be efficient in patients with some deficiencies in the homologous recombination machinery. However, a quick and reliable identification of patients who would benefit from such therapies remains a challenge. In particular, patients with tumors carrying variants of unknown significance (VUS) in homologous recombination genes do not currently benefit from PARP inhibitor treatments. In this study, we present an algorithm that may allow classification of these variants with regard to their impact on tumor responsiveness to PARP inhibitors. If validated on a larger patient sample, our algorithm would allow patients with tumors potentially responsive to PARP inhibitors to benefit from this therapy.PARP inhibitors yield interesting outcomes for patients with ovarian tumors harboring BRCA1 or BRCA2 mutation, but also with other tumors with homologous repair (HR) deficiency. About 40% of variants are variants of unknown significance (VUS), blocking the use of PARP inhibitors. In this study, we analyzed NGS data from 78 metastatic patients treated with PARP inhibitors. We tested NGS data and in silico predictions to classify VUS as potentially benign or deleterious. Among 41 patients treated with olaparib, three had tumors harboring benign and 26 pathogenic variants, while 12 had VUS. Progression-Free Survival (PFS) analysis showed that benign variants did not respond to olaparib whereas pathogenic variants were associated with a median PFS of 190 days. Surprisingly, median PFS of patients with VUS-carrying tumors suggested that some of them may be sensitive to PARP inhibitors. By testing different in silico predictions and variant allelic frequency, we obtained an algorithm predicting VUS sensitivity to PARP inhibitors for patients with a Performance Status below 3. Our work suggests that VUS in HR genes could be predicted as benign or deleterious, which may increase the number of patients eligible for PARP inhibitor treatment. Further studies in a larger sample are warranted to validate our prediction algorithm.

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors.

IntroductionTreatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.MethodsPatients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event.ConclusionsTreatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

The Feasibility of Using Biomarkers Derived from Circulating Tumor DNA Sequencing as Predictive Classifiers in Patients with Small-Cell Lung Cancer

Background: Exploring predictive biomarkers to individualize patients with small cell lung cancer (SCLC) remains challenging in clinical practice, and current imaging techniques cannot fully meet the clinical needs due to their inherent limitations. Methods: A total of 127 longitudinal biological DNA samples from 35 SCLC patients treated with first-line standard therapy were analyzed by capture-based targeted (average coverage for tissue and circulating tumor DNA (ctDNA) samples were 841× and 2670.5×, respectively) genome next-generation sequencing, which was designed to cover coding sequencing or hot exons of 1,021 genes frequently mutated in solid tumors. PyClone was used to infer the molecular tumor burden index (mTBI). Pre-treatment tumor tissues [T1] and serial plasma samples were collected (pre-treatment [B1], after two [B2], six [B3] cycles of chemotherapy and at progression [B4]). Findings: In total, 38 SCLC patients were enrolled with 35 patients included in the analysis set. The overall concordance rate between tissue and plasma sequencing in 30 patients with matched T1 and B1 samples was 66.5%. The median progression-free survival (PFS) was 9.8 months (95% confidence interval [CI]: 6.3-13.3). Patients with persisted RB1 and/or TP53 mutations at B2 demonstrated inferior PFS compared with others (5.2 months [95%CI: 3.8-6.6] vs. 13.1 months [95%CI: 9.8-16.4], p=0.06). The median PFS for patients with persisted RB1 mutations at B2 was significantly worse than the other two groups (4.2 months [95%CI: 2.8-5.6] vs. not reached, p<0.0001 and vs. 10.2 months, [95%CI: 6.3-14.1], p=0.001). The performance of mTBI monitoring was highly consistent with tumor imaging, and earlier mTBI elevation was observed in 64.7% of patients with B3 samples. In addition, the dynamic changes of mTBI from B4 to B1 were sensitive to predict new metastases, with sensitivity and specificity of 100% and 85.7% (95%CI: 50.8-120.7), respectively. Interpretation: Monitoring ctDNA based RB1 mutations and mTBI provided a feasible tool to predict prognosis of first-line therapy in SCLC, which guaranteed the development of prospective stratification in future trials. Trial Registration: This study was registered at the Chinese Clinical Trial Registry as ChiCTR1900023956. Funding: This study was supported by the National Key Research and Development Project (2019YFC1315704, to ZW), CAMS Innovation Fund for Medical Sciences (2017-I2M-1-005, to ZW), the National Natural Sciences Foundation (81871889, 82072586 to ZW) and Beijing Natural Science Foundation (7212084 to ZW). Declaration of Interest: The authors declare no potential competing interests. Ethical Approval: All procedures were conducted in accordance with the Declaration of Helsinki. This study was approved by the ethics committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China; approved No. 18- 151/1729).