Promising Progression-free Survival Research Articles

Abstract PR-04: Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2

Abstract Background: Poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitors have demonstrated efficacy in patients with platinum-sensitive pancreatic cancer who harbor germline BRCA 1/2 pathogenic variants (PVs). Whether PARP inhibitors are effective in a broader population of pancreatic cancer patients is still under investigation. Methods: This was a multicenter, single arm, open-label phase II trial (NCT03601923) investigating the use of the PARP inhibitor niraparib in patients with advanced pancreatic cancer. Eligible patients were required to have germline or somatic mutations in BRCA1, BRCA2, PALB2, ATM and/or CHEK2. Prior treatment with PARP inhibitors and prior progression on a platinum chemotherapy were not allowed, though patients could be included if they had progression on non-platinum based therapy. Patients were treated with weight-adjusted niraparib (200 mg or 300 mg) once daily on a 28-day cycle. The primary endpoint was 6-month progression free survival (PFS) rate (binary). Secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) by RECIST v1.1, and safety. Serial plasma samples were collected for circulating tumor DNA analyses. Results: Thirty-two patients (10 females [31%]; median age 67) were evaluable for the primary endpoint. Patients had a germline or somatic alteration in one or more of the following genes: ATM (n=14), BRCA2 (n=10), PALB2 (n=3), CHEK2 (n=4), or BRCA1 (n=2). There were 10 patients who received niraparib as maintenance therapy and 12 patients whose tumors previously progressed on a non-platinum-based chemotherapy. The 6-month PFS rate was 25% (90% CI: 13-41), rejecting the null hypothesis of a 17% 6-month PFS rate. The median PFS for the entire population was 2.0 months (90% CI: 1.7-3.7) and median OS was 10.2 months (90% CI: 8.2-13.2). The objective response rate was 14% (90% CI: 5-30%); 2 patients had a complete response, 2 patients had a partial response. Patients who never previously progressed on chemotherapy had a significantly longer median PFS (p=0.02) and OS (p=0.003) than patients who previously progressed on chemotherapy. Three patients with biallelic inactivation of ATM, who never progressed on prior lines of chemotherapy, were on niraparib for over 1 year (range 1 – 4 years). Reversion mutations restoring the reading frame in BRCA2 were identified in cell-free DNA in 3 patients with BRCA2 pathogenic frameshift variants. Additional putative resistance mutations in other DNA repair genes were identified and will be reported. Conclusions: Niraparib demonstrated a promising 6-month PFS rate and provided clinically meaningful benefit in patients with pancreatic cancer. The observation of prolonged benefit of three patients with biallelic ATM inactivation warrants further investigation. Acknowledgment: Funding for this study was provided by GSK. GSK was provided the opportunity to review a preliminary version of this abstract for factual accuracy. The authors are solely responsible for final content and interpretation. Citation Format: Brandon M. Huffman, Jett Crowdis, Matthew B. Yurgelun, Nora Horick, Yvonne Li, Huy Nguyen, Kalindi Parmar, Bose S. Kochupurakkal, Andrea Enzinger, Marios Giannakis, Nadine McCleary, Kimmie Ng, Anuj K. Patel, Kimberly J. Perez, Douglas A. Rubinson, Benjamin L. Schlechter, Harshabad Singh, Helen Lam, Kaitlyn Ramsey, Elizabeth Andrews, Leigh Culnane, Andrea Bullock, Ahmed Rattani, Jeffrey Clark, Mary Linton Peters, Brian M. Wolpin, Alan D. D'Andrea, Geoffrey I. Shapiro, Andrew J. Aguirre, James M. Cleary. Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-04.

A multicenter real-world study on the efficacy and safety of anlotinib-based treatment for metastatic breast cancer.

e13120 Background: Anlotinib is a multi-targeted small molecule receptor tyrosine kinase (RTK) inhibitor that inhibits angiogenesis. There is only one phase II study on the use of anlotinib in advanced breast cancer (MBC). Therefore, this study aims to analyze its efficacy and safety in the treatment of BC in the real world. It has been approved for the treatment of advanced non-small cell lung cancer and soft tissue sarcoma. There is limited research on the use of anlotinib in advanced breast cancer (MBC). Methods: This study retrospectively analyzed the clinical data of MBC patients who received anlotinib treatment at four domestic centers from January 2021 to December 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier analysis was used to analyze PFS and OS, and Cox regression model was used to analyze the hazard ratios (HRs) of anlotinib-based treatment on PFS and OS in different subgroups of patients. A p-value <0.05 was considered statistically significant. Results: A total of 153 MBC patients receiving anlotinib-based treatment were included from four centers. The median age was 51 years (range: 22-76), and the median number of prior lines of therapy was 3. The median PFS was 7.7 months (range: 5.2-10.1 months), and the median OS was 28.0 months (range: 21.4-34.9 months). The median ORR and DCR were 19.6% and 60.1%, respectively. The ORR for HR+/HER2- and triple-negative breast cancer patients was 11.6% and 28.8%, respectively, DCR for HR+/HER2- and triple-negative breast cancer (TNBC) patients was 55.8% and 59.6%, respectively. The median PFS was 9.0 months (range: 6.0-11.9 months) for HR+/HER2- patients and 5.3 months (range: 3.5-7.0 months) for TNBC patients, while the median OS was 33.0 months (range: 24.4-41.5 months) and 14.0 months (range: 9.5-18.4 months), respectively. In the subgroup analysis, age <60 years, initial stage IV disease, Ki67≤60%, and treatment with PD-L1 monoclonal antibodies-based regimen were associated with PFS benefit. ECOG <2 and treatment with PD-L1 monoclonal antibodies-based regimen were associated with prolonged OS. Among the 31 patients with brain metastases receiving anlotinib treatment, 11 had active brain metastases and 20 had stable brain metastases. The median PFS was 8.0 months. The intracranial ORR was 12.9%, and the intracranial DCR was 61.3%. No serious adverse events or treatment-related deaths occurred. Grade I/II adverse reactions included hand-foot syndrome (22.2%) and fatigue (19.6%), while grade III/IV adverse reactions included fatigue (6.5%) and decreased neutrophil count (5.2%). Three patients required dose reduction due to intolerable adverse reactions, and nine patients discontinued treatment. Conclusions: Anlotinib demonstrates good antitumor activity and safety in the treatment of MBC. When combined with chemotherapy or immunotherapy, it can improve PFS and OS without significantly increasing toxicity. In particular, it shows promising intracranial ORR and PFS in patients with brain metastases. Clinical trial information: NCT04541420 .

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( > 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .

Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.

The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option? This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%). The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were need in stage 1 (n=18) for the study to continue, and >19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-12.

Brief Report: Long-Term Follow-Up of Adjuvant Pembrolizumab After Locally Ablative Therapy for Oligometastatic NSCLC

IntroductionPatients with oligometastatic NSCLC benefit from locally ablative therapies (LAT); the role of adjuvant systemic therapies, however, remains less clear. In a single-arm, phase II clinical trial, we found that patients with oligometastatic NSCLC treated with a year of pembrolizumab after LAT had superior progression-free survival (PFS) compared with a historical control cohort. Herein, we present long-term follow-up on PFS and overall survival (OS). MethodsFrom February 1, 2015, to September 30, 2017, 45 patients with synchronous or metachronous oligometastatic (≤4 metastatic sites) NSCLC treated with LAT to all sites received adjuvant pembrolizumab every 21 days for up to 16 cycles. The primary efficacy end point was PFS from the start of pembrolizumab. Secondary end points included OS and safety. Median duration of follow-up was 66 months, and data cutoff was December 1, 2022. ResultsA total of 45 patients were enrolled and treated with pembrolizumab after LAT (median age, 64 y [range, 46–82]; 21 women [47%]; 31 with a solitary oligometastatic site [69%]). At the data cutoff, 32 patients had progressive disease, 19 patients had died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% confidence interval: 7.6–31.7 mo); median OS was not reached (95% confidence interval: 37.7 mo–not reached). OS at 5 years was 60.0% (SE, 7.4%). Metachronous oligometastatic disease was associated with improved OS and PFS through Cox proportional hazard models. ConclusionsPembrolizumab after LAT for oligometastatic NSCLC results in promising PFS and OS with a tolerable safety profile.

Combination of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600E-Mutated Thyroid Cancer.

BRAF mutations are detected in 30-80% of papillary thyroid cancer (PTC) cases. Dabrafenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer. This was a retrospective study to evaluate the efficacy of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of dabrafenib and trametinib. Between December 2019 and January 2022, 27 PTC patients including 8 patients with poorly differentiated or anaplastic transformation, received dabrafenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients. Dabrafenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Background : Double-unit cord blood transplantation (dCBT) is standard therapy for patients with acute myelogenous leukemia (AML) who do not have suitable adult donors. We & others have reported low relapse rates & high progression free survival (PFS) in dCBT recipients suggesting robust CB-derived graft-versus-leukemia effects. However, the efficacy of dCBT in high-risk AML as determined by ELN genetic risk & pre-transplant minimal residual disease (MRD) status has not been performed to date. Methods : All consecutive adult patients with AML who received first dCBT with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400) between 2014-2022 were analyzed. GVHD prophylaxis was with either Cyclosporine-A (CSA)/ Mycophenolate Mofetil (MMF) or CSA/MMF/Tocilizumab on an institutional protocol. Results : 63 patients (pts) (median age 49 years, range 23-63) were eligible for analysis (Table); 42 (67%) were CMV seropositive, 31 (49%) had non-European ancestry, & median HCT-CI was 2 (range 0-6). Most (n = 55, 87%) were in CR1, 5 (8%) in CR2, & 3 were relapsed or primary refractory at transplant (5-9% blasts). By ELN2022 genetic risk criteria, 8 pts had favorable, 29 intermediate, & 20 adverse risk AML (6 were missing ELN status). Of the 60 pts in CR, 36 were MRD- & 18 MRD+ by multicolor flow cytometry (6 had unknown/ indeterminate MRD status). Sixty-one of 63 pts engrafted for a 60-day cumulative incidence of 98% (95%CI:81-100). The median follow-up of survivors was 58 months (range 8-104 months). The 1- & 3-yr incidences of transplant-related mortality (TRM) were 13% (95%CI: 5.9-22) & 18% (95%CI: 9.6-29), respectively. The 1- & 3-year relapse incidences were 3.2% (95%CI: 0.6-9.9) & 8.6% (95%CI: 3.1-18), respectively. The 1- & 3-year OS were 87% (95%CI: 79-96) & 82% (95%CI:72-92) respectively, whereas the 1- & 3-year PFS were 84% (95%CI: 76-94) & 73% (95%CI: 63-85), respectively. When stratified by ELN2022 genetic risk, the 3-year relapse incidence was 0% in favorable, 10% (95%CI: 2.5-25) in intermediate & 13% (95%CI: 2-36%) in adverse risk AML patients. Pts with favorable risk AML had a 3-year PFS of 88% (95%CI: 67-100); the 3-year PFS was similar in patients with intermediate [68% (95%CI: 53-88)] or adverse [67% (95%CI: 48-93)] risk AML (Figure 1A). When stratified by MRD status, the 3-year relapse incidence was 8.4% (95%CI:2.1-20) in MRD- & 13% (95%CI: 1.9-34) in MRD+ patients. The 3-year PFS was similar in patients with AML in CR who were MRD- 80% (95%CI: 68-94) or MRD+ 76% (95%CI: 57-100), whereas all 3 relapsed/ refractory patients died of TRM (Figure 1B). Of 4 TP53-mutated AML patients, one relapsed, one died of TRM, & two are alive in remission. Conclusions: While retrospective, our findings highlight the low relapse rates & promising PFS in adult AML patients, including those with high risk features such as adverse-risk ELN genetic risk &/ or MRD positivity supporting robust CB-derived graft-versus-leukemia (GVL) effects. This observation, together with the mitigation of TRM in recent years due to the optimized transplant practices in adult dCBT (see Politikos et al, ASH 2023), makes intermediate intensity dCBT an attractive strategy for AML patients with a suitable dCB graft & high-risk disease. Our findings warrant prospective multi-center investigation with correlative studies to elucidate the biology of CB-derived GVL.

Safety and Efficacy of Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Updated Data from an Ongoing Single Arm Phase-II Investigator- Initiated Clinical Trial (PRIME Study)

Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In a phase 3 OPTIMISMM trial, Pomalidomide, Bortezomib, and Dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing Bortezomib, Pomalidomide and Dexamethasone combination in Newly Diagnosed Multiple Myeloma (NDMM). Initial data of 26 patients was presented as abstract in 63rd ASH Annual Meeting and Exposition. Current abstract is reporting the results of 46 patients with a longer follow up of this ongoing study. Objectives: Primary objective is to determine the efficacy of VPD regimen by measuring Minimal Residual Disease (MRD) assessment by flow-cytometry after 9 cycles of VPD. Secondary objectives are to determine response rates, PFS and safety of the regimen Methods: A prospective, single arm, phase II study from a tertiary care center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years as defined by the International Myeloma Working Group (IMWG) are being recruited in the study. The regimen consists of weekly Bortezomib 1.3mg/sq m, Pomalidomide 2 - 4mg once daily for 21days and Dexamethasone 20mg twice weekly, in a 28 days cycle for 9-12 cycles. Transplant patients planned for 9 cycles and non-transplant patients for 12 cycles of VPD. Eligible patients underwent High dose chemotherapy followed by Autologous HCT after 4-6 cycles of VPD. After Auto HCT 3-5 cycles of VPD given as consolidation therapy. After 9-12 cycles of VPD maintenance treatment given as per institutional practice. A 2-tube 8-colour antibody panel was used for MRD analysis using Flowcytometry (BD FACS CANTO-II) and analysed on Kaluza version. 1.3 software. A valve of < 0.001% was considered as MRD negative. Results: In this ongoing study, out of the proposed 50 patients, 46 patients were enrolled between April 2020 to June 2023. Median follow up is 24.5 months. The median age was 55 years (38-70), and gender ratio 1:1. At disease presentation, bone lesions was the commonest (91.3%, n 42) finding. The most common myeloma subtype was IgG Kappa in 43.5% (n 20). High risk cytogenetics were seen in 43.5% (n 20) and 43.5% (n 20) of patients were in RISS stage III (Table 1). Out of 46 patients 41 (89.1%) have completed 4 cycles and 30 (65.2%) patients have completed 9 cycles of VPD till last follow up (June, 2023). One patient had withdrawn consent, two patients were out of study due to increasing peripheral neuropathy (Grade 3). Five deaths occurred, 2 post cycle 8 and 3 after cycle 9. Four deaths were due to infections (COVID 19 and bacterial) and one due to progressive disease. Five patients underwent auto HCT (between Cycle 4 to 6). No patient failed stem cell mobilization, 2 patients required plerixafor in addition to G-CSF for mobilization. Table-1 shows drug-induced toxicity and response rates. Hematological toxicities were the commonest followed by fever, infections and skin rash. Majority of nonhematological adverse events were grade 1 to 2 and protocol was well tolerated. Protocol adherence was 97.8% (45/46 patients). After 4 cycles (n 43), 13 (30.2%) patients were in stringent complete response (sCR), 2(4.7%) in CR, 24 (55.8%) in very good partial response (VGPR) and 2 (4.7%) in partial response. After 9 cycles (n 35), 16 (45.7%) patients were in sCR, 2(5.7%) in CR and 11 (31.4%) in VGPR. Two (5.7%) patients had progressive disease (PD) and 3 patients were out of study due to consent withdrawn and toxicity. After 4 cycles of VPD 21 (48.8%) patients were MRD negative and MRD negative rate improved after 9 cycles to 74.3% (26 patients). Two years Progression Free survival (PFS) was 77.2% +/- 7.7% (Figure 1), disease free survival was 90.3% +/- 5.3% and overall survival (OS) was 83.1% +/- 7%. Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM and no clinically significant impact on stem cell mobilization or engraftment. Early efficacy signals are encouraging, and recruitment continued. VPD has shown improved depth of response (MRD negativity) and overall response rate. Early follow up results shows promising PFS and OS results. VPD may be a promising induction regimen instead of Dara VRD in resource constrain setting where Daratumumab is not readily accessible. Phase 3 randomized trials are the way forward to its clinical use in frontline setting.

Therapeutic effectiveness of anlotinib combined with etoposide in extensive-stage small-cell lung cancer: a single-arm, phase II trial

BackgroundAnlotinib plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC) achieves good efficacy, but there is still room for improvement. This clinical study examined the effectiveness of anlotinib plus etoposide for maintenance therapy in ES-SCLC.MethodsThe current single-arm, prospective phase II study was performed at Jiangsu Cancer Hospital (March 2019 to March 2022). After successful primary etoposide-based therapy, anlotinib was administered at 12 mg/day on days 1 to 14 of 21-day cycles until disease progression or consent withdrawal. All patients also received etoposide at 50 mg/day on days 1 to 14 of 21-day cycles for a maximum of six cycles. Progression-free survival (PFS) constituted the primary study endpoint. Secondary endpoints were overall survival (OS), objective remission rate (ORR), disease control rate (DCR), and safety. In addition, adverse events (AEs) were assessed.ResultsTwenty-eight patients were treated. Median PFS and OS were 8.02 (95%CI 5.36–10.67) and 11.04 (95%CI 10.37–11.68) months, respectively. Totally 9 and 18 participants showed a partial response and stable disease, respectively; ORR and DCR were 32.14% and 96.43%, respectively. The commonest all-grade AEs were fatigue (n = 11, 39.28%), hypertension (n = 11, 39.28%), loss of appetite (n = 9, 32.14%), oral mucositis (n = 7, 25.00%) and proteinuria (n = 6, 21.40%). Grade 3–4 AEs included fatigue (n = 4, 14.28%), hypertension (n = 2, 7.14%), hand and foot syndrome (n = 2, 7.14%), oral mucositis (n = 1, 3.57%), hemoptysis (n = 1, 3.57%), proteinuria (n = 1, 3.57%), gingival bleeding (n = 1, 3.57%), and serum creatinine elevation (n = 1, 3.57%).ConclusionMaintenance anlotinib plus etoposide achieves promising PFS and OS in clinical ES-SCLC.Registration numberChiCTR1800019421.

SABRSeq: A Randomized Phase Ib Trial of SABR Sequencing with Pembrolizumab in Metastatic Non-Small Cell Lung Cancer (NSCLC)

The optimal sequencing of stereotactic ablative body radiotherapy (SABR) with anti-PD1 checkpoint blockade is unknown. The purpose of SABRseq was to assess the toxicity of the combination of SABR delivered either before or after the commencement of pembrolizumab. The central hypothesis is that the treatment combination will have a safety profile that is clinically acceptable and demonstrate anti-tumor efficacy. Furthermore, we hypothesize that differences in systemic immune activation will be observed between treatment arms. This was a single institutional phase Ib randomized clinical trial (Trial ID NCT03307759). Eligible patients had metastatic NSCLC, ECOG performance 0-1, and had not received prior checkpoint immunotherapy, high-dose radiation (>36 Gy) within 6 months, or either systemic or radiation therapy within 4 weeks of randomization. Eligible patients had either TPS≥50% PD-L1 expression in the first-line or TPS≥1% PD-L1 expression with prior chemotherapy exposure. Patients were randomized to SABR before the commencement of pembrolizumab [ARM1] or SABR commencing after pembrolizumab [ARM2]. SABR was delivered in a single fraction of 18-20 Gy to 1-3 lesions. The primary endpoint was treatment-related adverse events (AE's) related to SABR and/or pembrolizumab. Secondary endpoints included best overall response (BOR), overall survival (OS), and progression-free survival (PFS). Translational objectives included the evaluation of longitudinal changes in immunological cellular subsets within peripheral blood to explore changes in systemic immunity and circulating tumor DNA (ctDNA) dynamics. Between December 2017 and December 2019, 13 patients were randomized. The median follow-up was 37 months. The study was closed early due to poor accrual. Median age was 66 years, with 11 patients (84%) having adenocarcinoma. Nine (69%) were enrolled in the first-line setting. The median [range] number of lesions was 6 [3-11]. The median [range] cycles of pembrolizumab delivered in ARM 1 was 13 [12-32] and ARM 2 was 9 [3-34]. Grade 3 treatment-related AEs were experienced in 0 of 5 patients in ARM1 and in 1 of 8 patients in ARM 2 (hyperglycemia). There were no grade 4 or 5 adverse events reported. The BOR by both RECIST and iRECIST criteria was CR in one patient, PR in seven patients, SD in five patients. Median (95% Cis) PFS was 12.4 months (6.3-21.0), and median (95% Cis) OS was 47.1 months (12.6-not reached; 2-year point estimate 62% [31-82]). Mass cytometry was used on serial peripheral blood samples to examine changes in the frequency of immune cells, changes in T cell activation, differentiation and functional polarization state. Targeted sequencing was performed to assess ctDNA. Translational outcomes will be presented. There was no evidence of a concerning safety signal from either SABR before or after start of pembrolizumab. The combination demonstrated activity with promising PFS and OS and is worthy of evaluation in larger randomized trials.

Efficacy and safety of pembrolizumab in advanced neuroendocrine tumors (NETs): A meta-analysis of clinical trials.

165 Background: Patients with recurrent or metastatic neuroendocrine tumors (NETs) have limited treatment options and a poor prognoses. Programmed death–ligand 1 (PD-L1) has been associated with the pathogenesis, progression, and prognosis of NETs. This article analyzes the efficacy and safety profile of PDL1 inhibitor Pembrolizumab in advanced NETs. Our objective is to identify all the clinical trials in which Pembrolizumab has been assessed in treating NETs and to evaluate the efficacy and safety profile in this patient population with high power. Methods: Systemic searches of PubMed, the Cochrane Library, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and serious adverse events (AEs). We calculated the pooled ORR for these studies using weighted pooled ORR = Σ (ORR_i * weight_i). We calculated the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). This statistical method was also used to calculate our study's pooled DCR, PFS, OS, and serious AEs. However, it is essential to note that the pooled data is only as reliable as the individual data estimates from each study and may be subject to bias or confounding factors. Results: Five clinical trials met the inclusion criteria, including patients with gastrointestinal, pancreatic, lung, and lower genital tract NETs. Outcome data were available for all five studies, comprising 177 patients with NETs who received Pembrolizumab as part of the treatment regimen (Table). The pooled ORR and DCR were 5.27% (95% CI 2.23-8.31) and 5.4% (95% CI 3-7.8), respectively. The pooled weighted PFS was 4.4 months, and pooled weighted OS was 23.3 months. These findings suggest that Pembrolizumab has a promising ORR, DCR, PFS, and OS. Safety was a secondary endpoint, and the pooled serious AEs were noted in 20.9% of patients. Conclusions: Pembrolizumab demonstrated statistically significant efficacy and safety profile in a subset of patients with NETs and was overall well-tolerated. In recent years, the combination strategy of tyrosine kinase inhibitors (TKI) with PDL-1 checkpoint inhibitors has shown promising clinical benefits in patients with various solid tumors. Further studies are needed to analyze the efficacy and safety of TKI with PD-L1 inhibitors in NETs. [Table: see text]

Efficacy of fibroblast growth factor receptor (FGFR) inhibitors therapy in advanced cholangiocarcinoma with FGFR genes alterations: A meta-analysis of phase II clinical trials.

54 Background: Fibroblast growth factor receptor ( FGFR) gene fusions and rearrangements are involved in the pathogenesis of approximately 10 to 16 percent of patients with cholangiocarcinoma. There is no meta-analysis available of phase 2 clinical trials of FGFR inhibitors in these patients. In this article, we analyze the efficacy of FGFR inhibitors in advanced cholangiocarcinoma with FGFR gene fusions or other rearrangements. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were Objective response rate (ORR), Disease control rate (DCR), Progression-free survival (PFS), and Overall survival (OS). We calculated the pooled ORR for these studies by using weighted average ORR = Σ (ORR_i * weight_i). Calculate the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). However, it is important to note that the pooled ORR is only as reliable as the individual ORR estimates from each study and may be subject to bias or confounding factors. This method was used to calculate the pooled DCR, PFS, and OS for our study as well. All data extraction and calculations were verified by three reviewers. Results: Eight phase II clinical trials met the inclusion criteria (1-8). Outcome data were available for all eight studies, comprising 562 patients with FGFR-positive advanced cholangiocarcinoma who received FGFR-targeted treatment regimens. The pooled objective response rate (ORR) and disease control rate (DCR) were 32.6% (95% CI 28.1-37.1) and 81.86% (95% CI 74.96-88.76), respectively. The pooled weighted progression-free survival (PFS) was 7.5 months, and pooled overall survival (OS) was 17.4 months. These findings suggest that FGFR-targeted treatment regimens have a promising ORR, DCR, PFS, and OS. Conclusions: FGFR inhibitors as a class in patients with advanced or metastatic cholangiocarcinoma with FGFR gene alterations showed clinically meaningful efficacy with durable objective responses. [Table: see text]

Long-term follow-up of “adjuvant” pembrolizumab following locally ablative therapy for oligometastatic non-small cell lung cancer.

9061 Background: Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) benefit from local ablative therapies (LAT); however, the role of adjuvant systemic therapies post LAT remains less clear. In a single-arm Phase II clinical trial (NCT02316002), we demonstrated that patients with OM NSCLC treated with adjuvant pembrolizumab following LAT had superior progression free survival (PFS) compared to historical controls. Here, we present long term follow-up on PFS and overall survival (OS). Methods: Patients with OM (≤ 4 metastatic sites) NSCLC treated with LAT to all sites received pembrolizumab every 21 days for up to 16 cycles from February 1, 2015 through September 30, 2017. Other key inclusion criteria included ECOG PS 0-1 and the absence of autoimmune diseases. Patients were eligible regardless of the number of prior therapies or PD-L1 status. Our study design was an intention to treat analysis with a null hypothesis that PFS would be equivalent to historical controls (6.6 months) compared with the alternative that PFS would be greater than 10 months. Assuming 42 patients enrolled over 2 years, we calculated 80% power to detect improvement in PFS with a 1-sided 5% significance level. Primary efficacy endpoint was PFS from the start of pembrolizumab and was defined as evidence of progressive disease (PD) via RESCIST v1.1 criteria, death, or last contact. Secondary endpoints included OS, determined by date of death or last contact, and safety. Cox proportional hazard models were performed to assess associations between clinicopathologic features and PFS or OS. Results: 51 patients enrolled in the study; 45 patients (median age, 64 years [range, 46-82]; 21 [47%] women; 31 [69%] with solitary OM site) received pembrolizumab following LAT. Patients received a median of 11 cycles of pembrolizumab; 18 (40%) patients completed 16 cycles. At the data cutoff (December 1, 2022; median f/u, 65.8 months), 32 patients had PD, 19 patients died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% CI, 7.6-31.7 months); median OS was not reached (95% CI, NR-NR). OS rate at 5 years was 60.0% (SE, 7.4%). Upon PD, 94% of patients received salvage therapies. Median OS from the time of PD was 39.7 months (95% CI, 13.8-65.6 months). Metachronous OM disease was significantly associated with improved OS (HR, 3.2 [95% CI, 1.5-6.7] and PFS (HR, 2.9 [95% CI, 1.2-7.5]) via multivariate Cox proportional-hazard models. The number of OM sites, CNS disease, nodal stage at diagnosis, or tumor PD-L1 status was not significantly associated with PFS or OS. We did not observe new safety signals for pembrolizumab following LAT aside from those previously reported. Conclusions: Pembrolizumab following LAT for OM NSCLC results in promising PFS and OS compared to historical experience with a tolerable safety profile. Further investigation of this approach with a randomized trial is warranted. Clinical trial information: NCT02316002 .

Clinical Activity of Olvimulogene Nanivacirepvec–Primed Immunochemotherapy in Heavily Pretreated Patients With Platinum-Resistant or Platinum-Refractory Ovarian Cancer

Patients with platinum-resistant or platinum-refractory ovarian cancer (PRROC) have limited therapeutic options, representing a considerable unmet medical need. To assess antitumor activity and safety of intraperitoneal (IP) olvimulogene nanivacirepvec (Olvi-Vec) virotherapy and platinum-based chemotherapy with or without bevacizumab in patients with PRROC. This open-label, nonrandomized multisite phase 2 VIRO-15 clinical trial enrolled patients with PRROC with disease progression following their last prior line of therapy from September 2016 to September 2019. Data cutoff was on March 31, 2022, and data were analyzed between April 2022 and September 2022. Olvi-Vec was administered via a temporary IP dialysis catheter as 2 consecutive daily doses (3 × 109 pfu/d) followed by platinum-doublet chemotherapy with or without bevacizumab. Primary outcomes were objective response rate (ORR) via Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and cancer antigen 125 (CA-125) assay, and progression-free survival (PFS). Secondary outcomes included duration of response (DOR), disease control rate (DCR), safety, and overall survival (OS). Twenty-seven heavily pretreated patients with platinum-resistant (n = 14) or platinum-refractory (n = 13) ovarian cancer were enrolled. The median (range) age was 62 (35-78) years. The median (range) prior lines of therapy were 4 (2-9). All patients completed both Olvi-Vec infusions and chemotherapy. Median follow-up duration was 47.0 months (95% CI, 35.9 months to NA). Overall, ORR by RECIST 1.1 was 54% (95% CI, 33%-74%), with a DOR of 7.6 months (95% CI, 3.7-9.6 months). The DCR was 88% (21/24). The ORR by CA-125 was 85% (95% CI, 65%-96%). Median PFS by RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and the PFS 6-month rate was 77%. Median PFS was 10.0 months (95% CI, 6.4-NA months) in the platinum-resistant group and 11.4 months (95% CI, 4.3-13.2 months) in the platinum-refractory group. The median OS was 15.7 months (95% CI, 12.3-23.8 months) in all patients, with a median OS of 18.5 months (95% CI, 11.3-23.8 months) in the platinum-resistant group and 14.7 months (95% CI, 10.8-33.6 months) in the platinum-refractory group. Most frequent treatment-related adverse events (TRAEs) (any grade, grade 3) were pyrexia (63.0%, 3.7%, respectively) and abdominal pain (51.9%, 7.4%, respectively). There were no grade 4 TRAEs, and no treatment-related discontinuations or deaths. In this phase 2 nonrandomized clinical trial, Olvi-Vec followed by platinum-based chemotherapy with or without bevacizumab as immunochemotherapy demonstrated promising ORR and PFS with a manageable safety profile in patients with PRROC. These hypothesis-generating results warrant further evaluation in a confirmatory phase 3 trial. ClinicalTrials.gov Identifier: NCT02759588.

Abstract P4-01-43: PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial

Abstract Background: Approximately 10% of patients with HER2-positive breast cancer have primary resistance to trastuzumab, leading to poor prognosis. Although several trials enrolled those hard-to-treat patients, there has been no strong evidence available for the clinical decision making. This multicenter phase 2 trial aimed to investigate the activity and safety of pyrotinib plus capecitabine only in those patients with trastuzumab-resistant, HER2-positive advanced breast cancer. Methods: Patients from 17 sites in China received pyrotinib 400 mg once a day and capecitabine 1000 mg/m2 twice a day on days 1-14 every 21 days until disease progression or intolerable toxicity. Based on the definitions used in prior clinical trials, primary trastuzumab resistance was defined as progression during trastuzumab treatment (Group 1) or within 12 months after completing trastuzumab treatment in the (neo)adjuvant setting (trastzuzumab should have been for ≥9 weeks, Group 2), or progression within 6 months after the initiation of trastuzumab treatment in the advanced setting (treatment should have been for ≥6 weeks, Group 3). The primary endpoint was progression-free survival (PFS). The study is registered with ClinicalTrials.gov, NCT04001621. Results: Between June 2019 and September 2021, a total of 100 patients enrolled; 35 (35.0%) patients had hormone receptor (HR)-positive disease, and 65 (65.0%) had HR-negative disease. Prior use of trastuzumab, pertuzumab and antibody-drug conjugate was reported in 100%, 21.0% and 2.0% of patients, respectively. By the data cutoff on July 10, 2022, the median follow-up duration was 23.4 months (95%CI, 20.5-25.6) with 66 PFS events documented. Median PFS was 11.8 months (95%CI, 8.4-15.1) in the overall population. Patients in Group 2 (n=49) had the longest median PFS of 17.8 months (95%CI, 13.8-not reached), which was significantly different from either 8.2 months (95%CI, 3.0-20.7; p = 0.001) in Group 1 (n=21) or 5.6 months (95%CI, 4.1-6.9; p < 0.001) in Group 3 (n=30). No significant difference in median PFS was observed in subgroup by HR status (HR-positive: 9.7 months [95%CI, 6.4-18.4]; HR-negative: 12.3 months [95%CI, 8.2-17.8]; p = 0.764). Objective response rate was 70.0% (95%CI, 60.0%-78.8%). Overall survival data was immature. The most common grade ≥3 treatment-emergent adverse events included diarrhea (24.0%), palmar-plantar erythrodysaesthesia syndrome (9.0%), neutrophil count decreased (7.0%), hypokalemia (5.0%), and decreased appetite (5.0%). No treatment-related deaths occurred. Conclusions: Pyrotinib plus capecitabine resulted in a promising PFS that crossed the pre-specified efficacy boundary in patients with HER2-positive advanced breast cancer who met the traditional definition of primary trastuzumab resistance. Patients in Group 2 had a significant longer PFS than those in either Group 1 or Group 3, highlighting the need to re-define primary trastuzumab resistance and to clarify efficacy of new anti-HER2 biologicals for each subpopulation. Citation Format: Xichun Hu, Jun Cao, Yue’e Teng, Hui-Ping Li, Lili Zhang, Quchang Ouyang, Weimin Xie, Yueyin Pan, Zhenchuan Song, Xiaoling Ling, Xiaohong Wu, Jingwei Xu, Li Li, Liping Ren, Hong Wang, Dongxian Zhou, Jing Luo. PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-43.

Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

BackgroundPyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients.MethodsWe performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers.ResultsA total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7–93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4–12.9 months) and median OS was 31.0 months (95% CI: 16.5–45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013).ConclusionsThe updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC.Trial registrationClinicalTrials.gov. (NCT01937689, NCT02361112).

Primary results of the ICONIC phase 2 trial of perioperative FLOT plus avelumab (FLOT-A) in operable oesophagogastric adenocarcinoma (OGA).

446 Background: ICONIC evaluated 4+4 cycles of FLOT-A (2-weekly standard FLOT with 10mg/kg of the anti-PDL1 antibody avelumab) for perioperative treatment of early-stage OGA. We report R0 resection rates, pathologic complete response rates (pCR), pathologic tumour regression grades (TRG) according to Mandard classification and progression free survival (PFS) data in the modified intention to treat population (mITT), and translational analyses. Methods: ICONIC is a single-arm phase II trial of FLOT-A in patients (pts) with ≥cT2-4 or N+ OGA. The pCR rate in surgical specimens was the primary endpoint. Response evaluation according to Mandard, R0 rates and PFS were among secondary endpoints. PD-L1 expression was assessed according to the combined positive score (CPS) with the 22C3 pharmDx kit. Results: The trial closed early after the pCR rate was 15% (95% CI: 49%-83%) once 34 pts in the mITT population (defined as pts who had 1-4 cycles FLOT-A and surgery) as the pre-specified aim to demonstrate a pCR rate of 25% in 40 pts was unlikely to be met. Baseline characteristics of the mITT population were: median age 64y, 79% male, 79% OG junction, 6% oesophageal, 15% stomach, 65% poorly differentiated, 79% T3/4, 59% N+. 91% of pts received all 4 pre-operative cycles and 97% of pts achieved R0 resections. PDL1 CPS ≥1 and CPS ≥5 were nevertheless associated with increased TRG3 and decreased TRG4/5 rates. 3/34 pts (9%) had hypermutated/MMRd tumours and after their exclusion, the association of higher CPS with better TRG3 and decreased TRG4/5 remained. With a median follow up duration of 15.8 months the 12-month PFS was 93.1% (95% CI: 75.1%-98.2%) which is promising compared to historic results with peri-operative FLOT. Conclusions: Although FLOT-A failed to increase pCR rates to 25%, there is a trend towards higher TRG3 and lower TRG4/5 in pts with PDL1 CPS≥1 and CPS≥5 and promising PFS indicate activity of immunotherapy in combination with FLOT chemotherapy. Translational and biomarker analyses by exome- and RNA-sequencing, and multiplex immune cell staining are ongoing and will be reported. Clinical trial information: NCT03399071 . [Table: see text]

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas.

Standard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors. All consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Among 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively]. In patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.