Longer PFS Research Articles

Impact of clinical and molecular features on efficacy and outcome of patients with non-small cell lung cancer receiving second-line osimertinib

BackgroundAlthough with the impressive efficacy, several patients showed intrinsic resistance or an unsatisfactory response to Osimertinib. We aim to explore the impact of clinical and molecular features on efficacy and outcome of patients with EGFR T790M-mutation non-small cell lung cancer (NSCLC) receiving second-line Osimertinib.MethodsPatients with EGFR T790M-mutant NSCLC who had acquired resistance to the first-generation EGFR TKI and then received Osimertinib as second-line treatment were included. Patients’ demographic and clinical information, as well as molecular data were extracted from electronic medical records. The impact of clinical and molecular features on treatment response and patients’ outcome were assessed.ResultsAmong the 99 patients, 60 patients were tissue/pleural effusion T790M positive and 69 patients were plasma positive with a median PFS of 12.1 m and 9.9 m (P = 0.25), respectively. In addition, median PFS were similar between patients of plasma T790M + and patients of plasma T790M- (P = 0.94). The Pearson correlation test showed no significant relationship between plasma T790M abundance and PFS (r = 0.074, P = 0.546). In subgroup analyses, PFS was significantly improved in elder patients (P = 0.009) and patients with longer PFS to the first-generation EGFR TKI (P = 0.0008), while smokers tended to have worse PFS compared with non-smokers (P = 0.064). PARP1 mutant-type patients had a worse PFS compared with wild-type group (P = 0.0003). Patients with MYC amplification also had a worse PFS than MYC wild-type patients (P = 0.016). A significant PFS shrinkage was observed in TMB-High group as 6.77 m, compared with 19.10 m in TMB-Low group. The multivariate Cox analysis revealed that years ≥ 65 was an independent positive feature for PFS, while PARP1 mutation and TMB-H were negative features for PFS.ConclusionIn conclusion, our findings in this study demonstrated that clinical and molecular features can be served as predictive biomarkers to stratify patients with EGFR T790M-mutant NSCLC receiving second-line Osimertinib.

Homologous recombination deficiency in diverse cancer types and its correlation with platinum chemotherapy efficiency in ovarian cancer

BackgroundHomologous recombination deficiency (HRD) is a molecular biomarker for administrating PARP inhibitor (PARPi) or platinum-based (Pt) chemotherapy. The most well-studied mechanism of causing HRD is pathogenic BRCA1/2 mutations, while HRD phenotype is also present in patients without BRCA1/2 alterations, suggesting other unknown factors.MethodsThe targeted next-generation sequencing (GeneseeqPrime® HRD) was used to evaluate the HRD scores of 199 patients (Cohort I). In Cohort II, a total of 85 Pt-chemotherapy-treated high-grade serous ovarian cancer (HGSOC) patients were included for investigating the role of HRD score in predicting treatment efficacy. The concurrent genomic features analyzed along HRD score evaluation were studied in a third cohort with 416 solid tumor patients (Cohort III).ResultsAn HRD score ≥ 38 was predefined as HRD-positive by analyzing Cohort I (range: 0–107). Over 95% of the BRCA1/2-deficient cases of Cohort I were HRD-positive under this threshold. In Cohort II, Pt-sensitive patients have significantly higher HRD scores than Pt-resistant patients (median: 54 vs. 34, p = 0.031) and a significantly longer PFS was observed in HRD-positive patients (median: 548 vs. 343 days, p = 0.003). Furthermore, TP53, NCOR1, and PTK2 alterations were enriched in HRD-positive patients. In Cohort III, impaired homologous recombination repair pathway was more frequently observed in HRD-positive patients without BRCA1/2 pathogenic mutations. The alteration enrichment of TP53, NCOR1, and PTK2 observed in Cohort II was also validated by the ovarian subgroup in Cohort III.ConclusionsUsing an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.

Durvalumab with chemoradiotherapy for limited-stage small-cell lung cancer

BackgroundThe current standard treatment for limited-stage small-cell lung cancer (LS-SCLC) is chemotherapy with concurrent chemoradiotherapy (CCRT). MethodsIn this single-arm phase II study, patients with LS-SCLC received four cycles of etoposide, cisplatin, and durvalumab every 3 weeks. Thoracic radiotherapy of 52.5 Gy in 25 once-daily fractions was started with the third cycle of chemoimmunotherapy. After CCRT plus durvalumab, patients received durvalumab consolidation therapy every 4 weeks for a maximum of 2 years after study enrolment. Prophylactic cranial irradiation (PCI) was recommended. ResultsFifty-one patients were enrolled, and 50 were included in the full analysis set. With the median follow-up duration of 26.6 months, the median PFS was 14.4 months (95% confidence interval: 10.3–NA), and the 24-month PFS rate was 42.0%. The median overall survival was not reached with a 24-month overall survival rate of 67.8%. The positive PD-L1 group (n = 22) was not associated with longer PFS (hazard ratio, 0.70; 0.31–1.58) and overall survival (0.64; 0.22–1.84) compared with the negative PD-L1 group (n = 20). Among the 43 patients who were candidates for PCI treatment, the PCI group (n = 22) had significantly fewer events of brain metastasis as the first failure sites compared to the no PCI group (n = 21) (13.6% vs. 42.9%, P = 0.033). There were several grade 3 or 4 adverse events which were well managed with appropriate supportive care. ConclusionsDurvalumab with CCRT for LS-SCLC exhibited promising clinical efficacy with a tolerable safety profile, prompting its validation in a randomized study. Trial registrationNCT03585998.

Effect and outcomes analysis of anlotinib in non-small cell lung cancer patients with liver metastasis: results from the ALTER 0303 phase 3 randomized clinical trial.

Liver metastasis (LM) is common in non-small cell lung cancer (NSCLC), and always predicted worse outcomes with no effective therapy. We aimed to evaluate the effects and prognosis in LM patients treated with anlotinib. The present study is a post hoc analysis based on a multicenter, double-blind, phase 3 randomized clinical trial which designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. A total of 437 patients were enrolled in present study, and 78 patients with LM. Patients with LM showed a worse outcome compared to those without LM (PFS median, 2.6 vs 4.2months), and OS (median, 5.6 vs 9.4months, both P < 0.0001). The anlotinib was associated with longer PFS (median, 3.0months) compared with placebo (median, 0.9months), with a hazard ratio (HR) of 0.23 (95%CI, 0.12-0.42; P < 0.0001). Furthermore, OS was marginally significantly better in anlotinib group (median 6.6months), compared with placebo (median 4.0months), HR 0.61 (95%CI, 0.36-1.02; P = 0.055). Multivariate analysis confirmed normal peripheral blood LDH/TBiL level predicted better PFS and OS, lower ECOG score acted as independently prognostic factor for superior OS. Anlotinib was more associated with hand-foot syndrome (7.7% vs 0) and serum TSH level rise (7.7% vs 3.8%) and well tolerated, all AEs were no more than grade 3. Patients with LM had a dismal prognosis, anlotinib could lead to a better PFS in pretreated NSCLC patients, which suggested anlotinib is a potential third-line or further therapy in these patients.

141O Durvalumab (D) ± tremelimumab (T) + platinum-etoposide (EP) in 1L extensive-stage (ES) SCLC: Characteristics of long-term survivors in the CASPIAN study

In the phase 3 CASPIAN trial, 1L D+EP significantly improved OS vs EP and OS benefit was sustained after >3 years median follow-up (HR 0.71; 95% CI 0.60‒0.86; nominal p=0.0003). Here we assess clinical and molecular characteristics of pts who experienced long-term survival in CASPIAN. 805 pts with ES-SCLC were randomised 1:1:1 to D+EP, D+T+EP or EP. In post-hoc analyses, clinical characteristics were assessed in long-term survivors (LTS; n=94), defined as pts still alive at the 22 Mar 2021 data cutoff (DCO; median follow-up 39.4 mo). PD-L1 expression and tissue tumour mutational burden (tTMB) were assessed in the biomarker evaluable populations (BEPs) according to OS landmark (18 and 36 mo). There were 44 (16%), 37 (14%) and 13 (5%) LTS in the D+EP, D+T+EP and EP arms, respectively. LTS had slightly higher incidence of some favourable prognostic factors at baseline; incidence of brain/liver mets was lower among LTS vs ITT, although they still occurred in some LTS (Table). More LTS received ≥4 cycles EP than ITT, with a higher median overall treatment exposure in the IO+EP arms. 46 (27 D+EP; 19 D+T+EP) LTS were ongoing D treatment at this DCO. ORR and 24-mo PFS rates were higher for LTS vs ITT in the IO+EP arms. Rates of serious AEs (SAEs) were similar in LTS and ITT (Table). In the D+T+EP arm only, incidence of PD-L1 expression on ≥1% of tumour cells (TC) or immune cells (IC) (but not tTMB >10 mut/Mb) was enriched in pts with OS ≥18 mo vs OS <18 mo (Table); enrichment was maintained with OS ≥36 mo (data will be presented). There were >3 times as many LTS in the D+EP arm vs the EP arm. LTS were more likely to have favourable prognostic characteristics than ITT, although some LTS had brain/liver mets at baseline. Notably, most LTS completed EP induction and, in both the IO+EP arms, had substantially greater overall treatment exposure, as well as achieving higher ORR and longer PFS, vs ITT. There was no evidence of cumulative toxicity based on SAEs.Table: 141OD+EPD+T+EPEPLTSITTLTSITTLTSITTn442683726813269Median age, yrs59.56259636363Male, %507170755468PS 0, %433746413133Brain mets, %710814010Liver mets, %204030441539Median overall exposure, wks15928160232019D dose delays, %75577659‒‒≥4 cycles EP, %*1008792819285Unconfirmed ORR, %†89799274697124-mo PFS, %†65116712553SAEs, %343254473136BEP, n/N (%)OS ≥18 moOS <18 moOS ≥18 moOS <18 moOS ≥18 moOS <18 moPD-L1 (TC or IC) ≥1%13/46 (28)25/106 (24)24/47 (51)30/110 (27)7/24 (29)25/103 (24)tTMB >10 mut/Mb16/29 (55)41/78 (53)16/30 (53)32/75 (43)4/16 (25)22/55 (40)*Based on etoposide†From 27 Jan 2020 DCO; RECIST data not collected after this DCO Open table in a new tab

Abstract P5-13-33: Longitudinal transcriptional profiling of CTCs in metastatic breast cancer patients receiving the CDK4/6 inhibitor Palbociclib to predict therapy response

Abstract Background: CDK4/6 inhibitors represent a new treatment option for metastatic (M), hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) patients. However, predictive markers have not been defined to decide who will benefit from CDK4/6 inhibitors. Circulating tumor cells (CTCs) represent the tumoral heterogeneity in real time and are available for molecular characterization via minimal-invasive sequential blood sampling. Here, we aim to identify biomarkers of resistance to Palbociclib by conducting transcriptional profiling of CTCs before therapy initiation (baseline) and after six months under treatment. Methods: Blood of 50 HR+/HER2-MBC patients drawn at baseline of Palbociclib plus endocrine treatment and blood of 20 HR+/HER2-MBC patients drawn before initiation of endocrine monotherapy, as well as blood samples of these 70 patients after six months under treatment will be analyzed. Patients with progressive disease within the first six months of treatment were defined as non-responders. Isolation of CTCs was conducted using positive immunomagnetic selection targeting EpCAM, EGFR and HER2 (AdnaTest EMT2/StemCell Select). cDNA was analyzed by a new multimarker qPCR panel utilizing QuantiNova LNA Probe assays targeting 25 genes. qPCR data was normalized to CD45 to substract the effect of contaminating leukocytes. Additionally, data was normalized to 20 healthy female donor controls to identify BC specific overexpression signals with a specificity of &amp;gt;90% for all targets. Consumables: QIAGEN, Germany. Results: We successfully established the multimarker qPCR according to the MIQE guidelines. Up to now, the binary mRNA overexpression signals of 25 targets in CTCs isolated at baseline were analyzed in 40 of the total 70 planned MBC patients. In detail, 24 of those 40 patients were treated with Palbociclib plus endocrine therapy, including seven responders and 15 non-resonders, while the 16 other patients were treated with endocrine therapy alone (seven non-responders and nine responders). In the entire cohort, STAT1 signals were significantly related to a decreased overall survival (p=0.0034) and NFKB1 signals correlated significantly with an increased progression free survival (PFS; p=0.027). In the Palbociclib group, CDK2, WWTR1 and YAP1 overexpression signals were more common in non-responders compared with responders. MLH1 and NFKB1 signals were more common in responders than in non-responders. In this cohort, MLH3 overexpression at baseline was significantly correlated with prolonged PFS (p=0.047) and the patient with the longest PFS (35 months) was the only patient with detectable ERBB4, JUN, CETN2 and TEAD2 signals. In the control group treated with endocrine therapy alone, signal prevalence of CXCR4 and STAT1 were increased in the non-responders versus responders and ABCC2, ESR1, FAT4 and FGFR1 signals were more frequently detected in the responders. Conclusion: Transcriptional profiling of CTCs represents a real-time snapshot of the disease complexity. Characterization of the CTCs isolated from blood drawn at baseline is promising for the identification of urgently needed predictive markers (here MLH3 overexpression), while characterization of CTCs isolated under treatment can elucidate the transcriptional dynamics and might be used as monitoring marker by differentiation of non-responders and responders. We will finalize CTC analysis of the entire cohort and will continue blood sampling of additional Palbociclib treated patients, also in the follow-up of the disease, to validate CTC MLH3 overexpression as predictive biomarker for CDK4/6 inhibitor treatment and moreover, to find further overexpression signals in CTCs relevant for MBC therapy management. Citation Format: Sabine Kasimir-Bauer, Charlotte Gruber, Oliver Hoffmann, Rainer Kimmig, Corinna Keup. Longitudinal transcriptional profiling of CTCs in metastatic breast cancer patients receiving the CDK4/6 inhibitor Palbociclib to predict therapy response [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 P5-13-33.

Abstract P1-17-09: Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic breast cancer

Abstract Background. Endocrine therapy plus CDK 4/6 inhibitors is the foremost treatment for hormone receptor (HR) positive metastatic breast cancers (mBC). Previously, we reported safety profiles of palbociclib use with grade 3 neutropenia in HR-positive mBC. Here, we investigated two cohorts’ patients who had received palbociclib with or without dose interruptions and/or reductions on afebrile grade 3 neutropenia in terms of efficacy outcomes. Patients and methods. The combined cohort of consecutive mBC patients who received palbociclib with letrozole in 1st line setting (in four major cancer centers in Republic of Korea) was reviewed. We classified patients into 4 groups: Group 1 (patients who maintained palbociclib dose on afebrile grade 3 neutropenia, representing limited dose modification scheme), Group 2 (patients who experienced any dose modification on afebrile grade 3 neutropenia, representing conventional dose modification scheme), Group 3 (patients without the event of afebrile grade 3 neutropenia), and Group 4 (patients who experienced only grade 4 neutropenia) within the first 5 cycles. The primary endpoint was PFS difference between Group 1 and Group 2, and secondary endpoints included PFS and overall survival difference in all groups, and safety profiles of each group. Results. A total of 434 eligible patients recruited from Jan 2017 to Sep 2020 were allocated into 4 groups; Group 1 (n=172, 40.1%), Group 2 (n=128, 29.5%), Group 3 (n=102, 23.5%), and Group 4 (n=30, 6.9%). The overall incidence of palbociclib dose reductions was 272 (62.7%) and dosing delay was 181 (42.2%) in all groups. The median time to first dose reduction for all eligible patients was 3 months (2-5 months) and the median time to second dose reduction was 9 months (2-30 months). At the 12th cycle of treatment, 70.5% (105/at-risk patients of 149) of Group 1 patients still remained on 125mg of palbociclib, whereas no patient was on 125mg dose level but 66.3% patients (65/at-risk patients of 98) were on 100mg in Group 2. At the median follow-up of 23.7 months (95% CI: 21.6-25.8), Group 1 patients showed significantly longer PFS than Group 2 patients (P-value = 0.036, 2-year PFS rate: 67.9% in Group 1 and 55.3% in Group 2). The OS between Group 1 and 2 was not significantly different. The favorable PFS trend of Group 1 over Group 2 was observed across all subgroups. The overall toxicity profiles were not significantly different between Group 1 and Group 2. Conclusion. Our study demonstrates that the clinical practice of limited dose modifications for palbociclib-related grade 3 neutropenia might have more therapeutic benefits than the conventional dose scheme without increasing toxicities. Permissive approach to afebrile grade 3 neutropenia and prospective clinical trials for this new dose scheme are warranted. Funding: This study was supported by a grant from Pfizer. Citation Format: Seul-Gi Kim, Min Hwan Kim, Sejung Park, Gun Min Kim, Jee Hung Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Jung Hwan Ji, Joon Jeong, Kabsoo Shin, Jieun Lee, Hyung-Don Kim, Kyung Hae Jung, Joohyuk Sohn. Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic breast cancer [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 P1-17-09.

Abstract P3-10-02: Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer

Abstract Purpose Capecitabine is one of a treatment option in anthracycline and taxane pre-treated metastatic breast cancer (MBC) patients. We have performed miRNA microarray of durable and poor responders to capcitabine, and compared with cell line miRNA expression profile (MCF-7, tamoxifen-resistant MCF-7 [MCF-TAM] cell line treated with 5-FU. Methods Between Jan 2006 to Jan 2021, 66 patients treated with capecitabine after anthracycline and taxane failure were enrolled. Twenty-three archival tumor tissues (11 durables and 12 poor responders, each) were collected and went through nCounter miRNA expression assay. MCF-7, tamoxifen resistant MCF-7 (MCF-TAM) cell line was treated with tamoxifen or 5-FU for proliferation assay and also went through nCounter miRNA expression assay. Results HR positive patients who received anti-estrogen treatment before capecitabine showed longer PFS (median 7.7 vs. 4.03 months, P=0.006). MCF-7 treated with tamoxifen and 5-FU showed decreased proliferation compared to 5-FU treated MCF-7. There was significant difference of miR-579-3p expression between durable and poor responders (log2FC -3.02, P=0.004). Tamoxifen-treated MCF-7 cell line showed upregulation of miR-579-3p compared to MCF-7. Tamoxifen + 5-FU treated MCF-7 cell line showed decreased expression of miR-579-3p compared to 5-FU treated MCF-7 cell line. MCF-7 cell line was treated with 5-FU and miR-579-3p. Compared to 5-FU only treated cell line, 5-FU + miR-579-3p treated cell line showed trends for decreased cell proliferation, suggesting that miR-579-3p may have chemo-sensitizing role during systemic chemotherapy. Based on miRNA database, authors hypothesized that MDM2 may be target protein of miR-579-3p and planning to perform further analysis. Conclusions Anti-estrogen treatment before capecitabine administration was associated to better survival in HR positive MBC. Anti-estrogen potentiated the effect of 5-FU in MCF-7. MiR-579-3p was upregulated in durable responders and tamoxifen treated MCF-7 cell line. Further study is planned to analyze the role of miR-579-3p and its potential target, MDM2 in breast cancer. Citation Format: Jieun Lee, Seung Yeon Joe, Ji-Sun Lee, Dong-Min Kim, Ahwon Lee. Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer [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 P3-10-02.

Final clinical outcome and biomarker analysis of sintilimab plus a bevacizumab biosimilar (IBI305) for advanced hepatocellular carcinoma: A phase Ib clinical trial.

455 Background: The combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) antibodies manifested high efficacy in advanced hepatocellular carcinoma (HCC), which still needs to be further verified. We aimed to evaluate the safety and activity of this strategy with different doses, as well as to explore potential predictive biomarkers. Methods: In this two-part phase Ib study, patients with advanced or metastatic HCC were enrolled. Part 1 was dose escalation trial with sintilimab plus bevacizumab biosimilar (IBI305) 7.5 mg/kg (initial dose) or 15 mg/kg (escalated dose). Part 2 was extension in each tolerable dose group. Peripheral blood samples and tumor tissue specimens were collected before treatment to detect serum cytokines and tumor immune microenvironment (TiME) by multiplexed bead immunoassays and multicolor immunofluorescence. Results: Fifty patients were enrolled in final analysis. Among all, IBI305 7.5 mg/kg was administered in 29 patients and 21 patients with 15 mg/kg. The most common adverse event suspected to be treatment-related was hypertension (32%), proteinuria (26%) and fever (26%). The incidence of the grade 3-5 adverse events in group 15 mg/kg was 28.6%, while 13.8% in 7.5 mg/kg group. Overall, the ORR was 34% (17/50) and the DCR reached to 78% (39/50). The median PFS was 10.5 months (95%CI, 8.4-12.7) and the median OS was 20.2 months (95%CI, 16.1 -24.3). The ORR for 7.5 mg/kg and 15 mg/kg were 31% and 38%, respectively. Further analysis showed that responder patients (CR+PR+SD≥12 weeks) had significantly higher level of serum CD137 than those with non-responder group (PD+SD≥12weeks) (median, 32.8 versus 19.8 pg/mL, P = 0.034). Patients with a high level of CD137 ≥ 31.8 pg/mL had longer PFS (mPFS:14.2 vs. 4.1months, P = 0.001) and OS (mOS: NR vs.15.6months, P = 0.023). In addition, the TiME analysis demonstrated that the density of M1 macrophages (CD68+CD163-) in stroma was related to efficacy (P = 0.033), longer PFS (P = 0. 024) and OS (P = 0.046). Conclusions: The sintilimab plus IBI305 is well tolerated and effective, IBI305 of 7.5 mg/kg could be also optional to some patients. The serum CD137 and M1 macrophages are potential predicting biomarkers for the combination therapy Clinical trial information: NCT04072679.

Outcomes of anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment for patients with advanced pancreatic adenocarcinoma: A retrospective analysis in China.

556 Background: Anlotinib, a novel small molecule multi-target tyrosine kinase inhibitor that can effectively inhibit VEGFR, PDGFR, FGFR, C-KIT et al, is proved to have anti-tumor angiogenesis and tumor growth inhibition effects. However, Anlotinib exploration on advanced pancreatic adenocarcinoma (PDAC) is still limited. The motivation of this work is to evaluate the efficacy and safety of anlotinib combined with nab-paclitaxel/gemcitabine in the first-line treatment of patients with advanced PDAC, and provide some evidence for the treatment regimens of advanced PDAC. Methods: This was a retrospective study in patients with advanced PDAC performed from Aug 17, 2019 to Apr 3, 2021. Patients who received anlotinib plus nab-paclitaxel/gemcitabine treatment were defined as Group 1, and patients who received nab-paclitaxel/gemcitabine as Group 2. The study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (P2021-13-21). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: In this work, 33 patients were included, with 17 cases in Group 1 and 16 cases in Group 2. The median PFS (mPFS) of Group 1 and Group 2 were 5.0 (95% Cl, 4.97-5.94) months and 2.7 (95% Cl, 2.4-3.3) months, respectively ( P = 0.0220). The median OS (mOS) of Group 1 and Group 2 were 9.0 (95% Cl, 6.55-11.45) months and 6.0 (95% Cl, 1.08-10.92) months, respectively ( P=0.006). The PFS rate in 3 and 6 months and the OS rate in 6 and 12 months of Group 1 were significantly higher than that of Group 2. The most common grade 3 treatment related AEs (trAEs) were hematological toxicity, with 35.29% in Group1 and 31.25% in Group 2. Non-hematological toxicity were hypertension, hand-foot syndrome and diarrhea. No grade 3 or higher non-hematologic toxicity was observed in all patients. Conclusions: Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment demonstrates encouraging efficacy and manageable AE in patients with advanced PDAC. Clinical outcomes are improved with longer PFS and OS in anlotinib plus chemotherapy group. More data are needed to confirm the long-term efficacy and safety of anlotinib plus nab-paclitaxel/gemcitabine in advanced PDAC patients.

Genomic profiling as a response predictor of second-line treatment in advanced gastric cancer patients: Post-hoc analyses of two phase Ib/II trials.

351 Background: Targeted panel next-generation sequencing (NGS) is now actively performed in clinics to guide treatment decisions for advanced cancer patients. However, NGS profilings of advanced gastric cancer (AGC) do not provide relevant genomic biomarkers that could predict response to second-line treatment for AGC patients yet. Methods: Two paclitaxel-based phase Ib/II trials as a second-line treatment for AGC patients were included: GSK2636771 (PI3Kβ selective inhibitor) and paclitaxel for AGC patients with PI3K/Akt pathway alterations (PTEN trial, NCT02615730, presented at GI ESMO 2021) and nivolumab and paclitaxel for EBV-related, dMMR/MSI-H or PD-L1 positive AGC (K-umbrella-003 trial, NCT02951091, presented at AACR 2021). Pre-treatment tumor tissue samples from two trials were subjected to the in-house panel sequencing using CancerMaster Panel V2 (Kwon et al., GI ASCO 2021) that covers 524 genes for single nucleotide variants, 143 for copy-number variations, and 18 for fusions. Baseline genomic alterations were compared with each patient’s response and survival. Oncogenic signaling pathways were annotated manually according to previous reports. Tumor mutation burden (TMB) and Human leukocyte antigen (HLA) profilings were also performed. Results: Baseline tumor tissues from 54 patients (24 from PTEN trial, 30 from K-umbrella-003 trial) were available for NGS. In patients treated with GSK2636771 and paclitaxel, patients with PIK3R1 M326I mutation (n = 3) showed longer PFS (8.1 vs 2.8 months, P= 0.041), and patients without MYC Q48H (n = 13) showed better PFS (4.8 vs 2.6 months, P= 0.013). Genetic alterations in epigenetic pathway were found in 13 patients (54.2%) and showed worse PFS (2.8 vs 5.0 months, P = 0.04). In patients treated with nivolumab and paclitaxel, patients with RTK/RAS pathway alterations excluding deletions (n = 21, 70%) showed significantly longer PFS (4.1 vs 2.6 months, P = 0.0085), and patients with HLA-A02 supertype (n = 11, 36.7%) showed significantly longer PFS (12.4 vs. 2.7 months, P = 0.0068). In both studies, TMB-high was not related to the survival and there were no common predictive genomic alterations. Conclusions: We observed that specific NGS-based genomic alterations such as single gene mutations, altered signaling pathways and HLA genotyping were potential predictors of each targeted agent or immunotherapy as a 2nd line treatment of AGC patients, regardless of paclitaxel. Further correlative studies within AGC trials for exploring predictive biomarkers are warranted. Clinical trial information: NCT02615730; NCT02951091.

Efficacy of ICIs on patients with oncogene-driven non-small cell lung cancer: a retrospective study

Aim: The objective of our study was to assess the efficacy of immune checkpoint inhibitors (ICIs) on patients with non-small-cell lung cancer (NSCLC) harboring oncogenic alterations. Methods: We retrospectively enrolled patients with advanced non-squamous NSCLC who were treated with anti-PD-1-based monotherapy or combined immunotherapy. Major characteristics including PD-L1 expression, treatment, and survival were analyzed. Results: In total, 309 non-squamous NSCLC patients with a median age of 61 years (range 20-88 years) including 70.9% male were retrospectively enrolled. The molecular alterations involved epidermal growth factor receptor (EGFR) (n = 81), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (n = 31), anaplastic lymphoma kinase (ALK) (n = 1), human epidermal growth factor receptor 2 (HER2) (n = 12), V-raf murine sarcoma viral oncogene homolog (BRAF) (n = 2), rearranged during transfection (n = 4), and c-ros oncogene 1 (ROS1) (n = 3). In the EGFR subset, the ORR was 30.9% (n = 81) and PFS was significantly shorter than WT group (median PFS: 5.7 months vs. 7.1 months; P = 0.0061). In subgroup analyses, ICI combined therapy was significantly correlated with a longer PFS compared with ICI monotherapy (median PFS: 7.7 months vs. 4.7 months; P = 0.0112). In KRAS patients, ORR was 51.6% (n = 31). No significant difference was found in subgroup analyses. The ORR and PFS were 16.7% (n = 12) and 28.6% (n = 7), 7.8 months and 9.0 months for HER2 and EGFR Exon20 insertion patients, respectively. Three ROS1 patients were enrolled with a PFS of 16.0, 34.2, and 45.0 months individually, and one ALK patient with PFS of 4.4 months was identified. No response was found in two BRAF patients. Conclusion: ICI-based combination therapy can bring benefit to patients with EGFR-mutant NSCLC. ICI-based combination therapy could be considered for patients with ROS1 rearrangement, HER2 mutation and EGFR Exon20 insertion NSCLC.

Chasing a\xa0rarity: a\xa0retrospective single-center evaluation of prognostic factors in primary gliosarcoma

Background and purposePrimary gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma multiforme. We performed a single-center analysis to identify prognostic factors.Patients and methodsWe analyzed the records of 26 patients newly diagnosed with primary WHO grade IV GS. Factors of interest were clinical and treatment data, as well as molecular markers, time to recurrence, and time to death.ResultsMedian follow-up was 9 months (range 5–21 months). Gross total resection did not lead to improved survival, most likely due to the relatively small sample size. Low symptom burden at the time of diagnosis was associated with longer PFS (P = 0.023) and OS (P = 0.018). Median OS in the entire cohort was 12 months. Neither MGMT promoter hypermethylation nor adjuvant temozolomide therapy influenced survival, consistent with some previous reports.ConclusionIn this retrospective study, patients exhibiting low symptom burden at diagnosis showed improved survival. None of the other factors analyzed were associated with an altered outcome.

Peak Absolute Lymphocyte Count Post CAR-T Is Associated with Clinical Response and Survival Outcome in Aggressive Lymphoma

IntroductionChimeric antigen receptor T cell (CAR-T) expansion has been consistently identified as a predictor of clinical response. However, there are no clinically available test to measure CAR-T presence after infusion for the FDA approved CAR-T therapy. We hypothesize that the lymphocyte expansion which can be readily measured as absolute lymphocyte count (ALC) in blood count differential could be a clinically accessible surrogate for CAR-T expansion in patients who receive FDA approved CD19 CAR-T to treat aggressive B-cell non-Hodgkin lymphoma (NHL). We examined the ALC levels in the first 2 weeks after CAR-T infusion and correlation with clinical outcomes in NHL patients who received CAR-T at our institution.MethodsRecords were reviewed for patients who received CAR-T between 6/2016 and 1/2021 at Mayo Clinic, Rochester. CAR+ T cells were identified by flow cytometry using an anti-FMC63 antibody. Receiver operator curve was generated using nominal logistic regression to predict complete response (CR) as best response. Progression-free survival and overall survival were calculated using Kaplan-Meier method and between-group differences were assessed using log-rank test. Continuous variables were compared using wilcoxon text and categorical variables were compared using chi-square test.ResultsAmong the 87 patients who received CAR-T for NHL, majority of the pts received axicabtagene ciloleucel (86, 99%). The highest ALC level (ALC peak) in the first 15 days were identified for all patients and median ALC peak was 0.44 X10 9/L (range, 0 - 2.55x10 9/L). The median time to ALC peak was 10 ±3 days. Increasing ALC peak levels correlated with increased CAR+ T cells in blood measured by flow cytometry (n=16, R=0.63, p=0.0008). Using ROC analysis, an ALC peak level of 0.67 was identified as the cut point for best association with CR (AUC=0.68, p=0.0004). Baseline demographics were similar between the high ALC peak (N=35) and low ALC peak (N=52) groups, as shown in Table 1. There was no difference in the incidence, high grade, or duration of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) between the two groups (Table 2). Patients who received a higher cumulative dose of steroid for management of CRS and ICANS had lower ALC peak. A higher ALC peak was associated with an increased CR rate and durable CR at month 6. Similarly, a higher ALC peak was associated with increased progression-free survival (PFS, 6.4 months vs. 2.7 months, p=0.004) and overall survival (OS, 31 months vs. 12 months, p=0.04), as shown in figure 1.ConclusionGiven the typical CAR-T expansion seen in the first 2 weeks post infusion, ALC peak in the first 15 days is a clinically accessible, reliable surrogate for CAR-T expansion and predicts durable CR and longer PFS, OS.This study was supported in part by the Mayo Clinic Center for Individualized Medicine, Bernard E. and Edith B. Waterman, Henry J. Predolin Foundation and other generous benefactors of Mayo Clinic. [Display omitted] DisclosuresBennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Merck: Research Funding; Sorrento: Consultancy; Juno: Consultancy.

Phase II trial of nab-paclitaxel in metastatic breast cancer patients with visceral metastases

BackgroundVisceral metastases account for 48–67% of metastatic breast cancer (MBC) patients and presage a worse overall survival. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. This phase II trial was conducted to explore the efficacy and safety of nab-paclitaxel in such a high-risk group of patients.MethodsIn this prospective, single-center, open-label, phase II study, MBC patients with visceral metastases (N = 80) received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days).ResultsThe median PFS was 5.1 months (95% CI: 4.2–6.0 months), with an ORR of 33.8% (95% CI 21.3–43.8%) and CBR of 66.2% (95% CI 56.3–75.0%). In univariate analysis, patients with premenopausal status had a trend of better treatment outcome. Multivariate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95% CI 0.12–0.83, P = 0.019) and first line treatment (adjusted HR 0.37, 95% CI 0.17–0.81, P = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade ≥ 3 toxicities of neutropenia (16.3%) and sensory neuropathy (3.7%).ConclusionsThis phase II trial documented satisfactory efficacy and safety of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in first line therapy had better treatment outcome. For patients with premenopausal status or brain metastasis, further alternatives (for example, combined chemotherapy or targeting therapy) might be required. This study also demonstrated the efficacy and safety of 125 mg/m2 nab-paclitaxel among Asian patients.Trial registrationThis research is registered under clinicaltrials.gov (NCT 02687490, February 22, 2016).

Prognostic value of pre-irradiation FET PET in patients with not completely resectable IDH-wildtype glioma and minimal or absent contrast enhancement

In glioma patients, complete resection of the contrast-enhancing portion is associated with improved survival, which, however, cannot be achieved in a considerable number of patients. Here, we evaluated the prognostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in not completely resectable glioma patients with minimal or absent contrast enhancement before temozolomide chemoradiation. Dynamic FET PET scans were performed in 18 newly diagnosed patients with partially resected (n = 8) or biopsied (n = 10) IDH-wildtype astrocytic glioma before initiation of temozolomide chemoradiation. Static and dynamic FET PET parameters, as well as contrast-enhancing volumes on MRI, were calculated. Using receiver operating characteristic analyses, threshold values for which the product of paired values for sensitivity and specificity reached a maximum were obtained. Subsequently, the prognostic values of FET PET parameters and contrast-enhancing volumes on MRI were evaluated using univariate Kaplan–Meier and multivariate Cox regression (including the MTV, age, MGMT promoter methylation, and contrast-enhancing volume) survival analyses for progression-free and overall survival (PFS, OS). On MRI, eight patients had no contrast enhancement; the remaining patients had minimal contrast-enhancing volumes (range, 0.2–5.3 mL). Univariate analyses revealed that smaller pre-irradiation FET PET tumor volumes were significantly correlated with a more favorable PFS (7.9 vs. 4.2 months; threshold, 14.8 mL; P = 0.012) and OS (16.6 vs. 9.0 months; threshold, 23.8 mL; P = 0.002). In contrast, mean tumor-to-brain ratios and time-to-peak values were only associated with a longer PFS (P = 0.048 and P = 0.045, respectively). Furthermore, the pre-irradiation FET PET tumor volume remained significant in multivariate analyses (P = 0.043), indicating an independent predictor for OS. Our results suggest that pre-irradiation FET PET parameters have a prognostic impact in this subgroup of patients.

Diagnostic and prognostic value of FDG PET-CT in patients with suspected recurrent thymic epithelial tumors

This study aimed to evaluate the diagnostic and prognostic value of FDG PET/CT in patients with suspected recurrent thymic epithelial tumors (TETs). We retrospectively reviewed 83 patients with histopathologically proven TETs (50 thymomas; 33 thymic carcinomas) who underwent FDG PET/CT after surgery. The sensitivity and specificity of FDG PET/CT in detecting recurrence were calculated. The progression-free survival rate (PFS) was calculated by the Kaplan–Meier method. FDG PET/CT results were positive in 50 patients and negative in 33. Recurrent TETs were confirmed in 40 of 50 patients with positive PET/CT findings. The sensitivity and specificity of FDG PET/CT were 100% and 76.7%, respectively. Disease progression occurred in 28 patients during the follow-up. FDG PET/CT showed added prognostic value over the Masaoka stage and histopathology. Among patients with the same Masaoka stage, negative PET/CT was significantly associated with better PFS (P < 0.001). Similarly, among patients with the same histopathology, negative PET/CT was also associated with a significantly longer PFS (P < 0.001). FDG PET/CT demonstrated a good diagnostic performance in patients with recurrent TETs and had an important prognostic value in assessing the risk of disease progression.

Identification and validation of tissue or ctDNA PTPRD phosphatase domain deleterious mutations as prognostic and predictive biomarkers for immune checkpoint inhibitors in non-squamous NSCLC

BackgroundWith the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in non-small cell lung cancers (NSCLC), identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatase receptor-type (PTPRs) and ICIs responses are unknown.MethodsWhole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1 therapy was carried out with corresponding clinical data collected as a discovery cohort to find the associations of PTPR mutations and ICI responses. Three validation cohorts consolidated by 7 public cohorts of 1920 NSCLC patients with WES or target sequencing data of tumor tissue-derived DNA or circulating tumor DNA (ctDNA) and relevant clinical data were applied as validation cohorts. The lung adenocarcinoma (LUAD) cohort (n=586) in The Cancer Genome Atlas (TCGA) database was used for analyzing the potential anti-tumor immunologic mechanisms.ResultsWith the highest mutation frequency among all PTPRs, PTPRD mutations in non-squamous NSCLC (ns-NSCLC) were linked to longer progression-free survivals (PFS, 324 vs 63 days, hazard ratio (HR)=0.36, p= 0.0152) and higher objective response rate (ORR, p=0.0099). In validation cohort 1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.0184) and ORR (p=0.013). In validation cohort 2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable overall survivals (OS, over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort 3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD’s prediction efficiency. In addition, in validation cohort 3, ctDNA phosphatase-mut also functioned as a predictive biomarker helping identify patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed that phosphatase-mut was independent on PD-L1 expression and tumor mutation burden (TMB) to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients.ConclusionsTissue or ctDNA PTPRD phosphatase domain deleterious mutations might function as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients, independent on TMB or PD-L1 expression.

"Highly Exposed Chinese Herbal Medicine" Combined With Apatinib as Maintenance Treatment Following First-Line or Second-Line Chemotherapy for Extensive-Stage Small-Cell Lung Cancer: A Single-Arm, Prospective Study.

This study aimed to evaluate the efficacy and safety of “highly exposed Chinese herbal medicine” combined with apatinib as maintenance treatment following first-line or second-line chemotherapy in patients with ES-SCLC. A total of 23 patients with ES-SCLC were included in this single-arm prospective study (ChiCTR2100045255). “Highly exposed Chinese herbal medicine” combined with apatinib was administered each day after the chemotherapy for maintenance treatment. The primary endpoint of the study was median PFS, while the secondary endpoints included median OS, DCR, ORR, AE, and the association of “highly exposed Chinese herbal medicine” with PFS and OS. Three and 16 patients achieved partial response (PR) and stable disease (SD), respectively, and four patients were with disease progression (PD). The ORR of the patients was 13.0%, DCR was 83.0%, median PFS was 5.0 months, and median OS was 18.0 months. The major AE included secondary hypertension and hand-foot syndrome. Oral intake of Chinese herbal medicine for ≥ 6 months was associated with longer PFS. Hand-foot syndrome was an independent predictive factor for PFS. The statistical analysis suggested no independent influencing factors for OS. “Highly exposed Chinese herbal medicine” combined with apatinib is effective and relatively safe as the maintenance treatment for ES-SCLC patients who undergo first-line or second-line chemotherapy.

Influence of scalp block on oncological outcomes of high-grade glioma in adult patients with and without isocitrate dehydrogenase-1 mutation

High-grade gliomas are notorious for a high recurrence rate even after curative resection surgery. Studies regarding the influence of scalp block on high-grade gliomas have been inconclusive, possibly because the condition’s most important genetic mutation profile, namely the isocitrate dehydrogenase 1 (IDH1) mutation, had not been analyzed. Therefore, we conducted a single-center study including patients with high-grade glioma who underwent tumor resection between January 2014 and December 2019. Kaplan–Meier survival analysis revealed that scalp block was associated with longer progression-free survival (PFS; 15.17 vs. 10.77 months, p = 0.0018), as was the IDH1 mutation (37.37 vs. 10.90 months, p = 0.0149). Multivariate Cox regression analysis revealed that scalp block (hazard ratio: 0.436, 95% confidence interval: 0.236–0.807, p = 0.0082), gross total resection (hazard ratio: 0.405, 95% confidence interval: 0.227–0.721, p = 0.0021), and IDH1 mutation (hazard ratio: 0.304, 95% confidence interval: 0.118–0.784, p = 0.0138) were associated with better PFS. Our results demonstrate that application of scalp block, regardless of IDH1 profile, is an independent factor associated with longer PFS for patients with high-grade glioma.