12-week Progression-free Survival Research Articles

Safety and efficacy of complement factor H (CFH) inhibitor GT103 in advanced non-small cell lung cancer (NSCLC): Results of a phase Ib first in human dose escalation study.

e14588 Background: CFH is a complement regulatory protein that protects cells from alternative complement pathway activation. Neutralizing antibodies against CFH on tumor cells increase deposition of C3b, facilitate antibody-dependent-cellular phagocytosis and complement dependent cytotoxicity, inhibit tumor growth, and modulate anti-tumor immunity. GT103 is a first-in class, fully human-derived IgG3 anti-CFH monoclonal antibody that recognizes a tumor specific epitope on CFH and has shown anti-tumor activity in preclinical models. Methods: We conducted a phase Ib, first-in-human, dose escalation trial evaluating safety and preliminary efficacy of GT103 in patients (pts) with advanced NSCLC refractory to standard therapies. Pts received GT103 intravenously across six dose levels/schedules following 3+3 design. Primary objectives were to determine maximum tolerated dose (MTD), recommended phase II dose (RP2D), and pharmacokinetic profile of GT103. Secondary objectives were to assess objective response rate, progression free survival (PFS), and overall survival (OS). Here we present updated safety and efficacy results of the study. Results: 31 pts were enrolled from 6/2020 to 9/2023 (median age 63yrs (range, 23-79), 61% had adenocarcinoma, 32% had previously treated brain metastasis). MTD was not reached. Treatment related AEs (TRAEs) observed in ≥10% pts included fatigue (19%), anemia (16%), diarrhea (16%), and nausea (13%). 3 pts developed ≥ grade 3 TRAE, including acute kidney injury, decreased lymphocyte count, and anemia. The best treatment response was stable disease in 9 (29%) pts. Median(m) PFS and mOS were 6 weeks (95% CI 6.0-6.1) and 25.7 weeks (95% CI 19.1-30.6), respectively. 24-week PFS and OS were 9.7% (95% CI 2.5-22.9%) and 50.6% (95% CI 31.9-66.6%), respectively. PD-L1 expression was available in 25 pts. No statistically significant difference (p=0.33) was noted in mPFS between PD-L1 positive (TPS > 1%) vs negative (TPS ≤1%) pts. KRAS and EGFR mutation status was available for 22pts. mPFS and mOS were numerically longer in pts with KRAS positive vs negative disease. While there was no difference in mPFS, 24-weeks PFS was 0 vs 16.7% (95% CI 4.1-36.5%) EGFR MUT vs wild type disease. Biomarker analysis of complement regulatory proteins, FcGR expression and polymorphisms, and changes in sC5b-9 is underway. Conclusions: GT103 was well tolerated across all dose levels. The RP2D of 10mg/kg IV every 3 weeks was selected, although PK modeling will be performed to optimize the dosing schedule. Encouraging anti-tumor activity was seen in heavily pretreated pts with advanced NSCLC with a subset of patients experiencing stable disease lasting for longer than 6 months. Additional biomarker analysis is ongoing. A phase II trial combining GT103 with pembrolizumab in pts with advanced NSCLC is currently enrolling. Clinical trial information: NCT04314089 .

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

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

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

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

REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas

BackgroundNovel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs. Patients and methodsAdult patients with IDHm WHO grade 3–4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria. ResultsFrom July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15–44.9%). Median PFS and OS were 1.84 (CI95% 1.81–5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies. ConclusionsWe report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.

TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .

Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab

Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

Real-World Results of Raltitrexed Combined with S-1 and Bevacizumab in Heavily Pretreated Metastatic Colorectal Cancer.

Treatment options for refractory metastatic colorectal cancer (CRC) are scarce. This retrospective study aimed to evaluate the efficacy and safety of raltitrexed combined with S-1 and bevacizumab in patients with heavily pretreated metastatic CRC in a clinical real-world setting. Records of patients with metastatic CRC refractory to standard therapies who initiated raltitrexed plus S-1 and bevacizumab from October 2017 to December 2021 were retrospectively reviewed at our institution. The study endpoints included median overall survival (OS), overall response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and adverse events (AEs). Forty-four patients with metastatic CRC, who had previously undergone standard chemotherapy received the regimen comprising raltitrexed plus S-1 and bevacizumab. As of March 2022, the median follow-up was 23.2 months (95% confidence interval 15.8-30.6). The median OS and median PFS were 13.5 (95% CI 9.9-17.1) and 4.7 months (95% CI 3.6-5.8), respectively, with a 16-week PFS rate of 60.9%. Among 43 patients with measurable lesions, the ORR and DCR were 7.0% (3/43) and 65.1% (28/43), respectively. Patients without peritoneal metastases (P = 0.003, hazard ratio 0.160, 95% CI 0.048-0.531), lower carcinoembryonic antigen level (≤42.8 ng/mL) (P = 0.039, HR 0.382, 95% CI 0.153-0.952), and no previous treatment with both vascular endothelial growth factor inhibitors (VEGF) and S-1 (P = 0.020, HR 0.215, 95% CI 0.059-0.785) had better OS. The incidence of any grade of treatment-related AEs was 88.6%, most of which were mild to moderate, and no treatment-related deaths occurred. Raltitrexed combined with S-1 and bevacizumab shows promising antitumor activity and safety and could be an alternative for patients with metastatic CRC who are refractory or intolerant to standard therapy.

BAYONET trial: A multicenter phase II trial of staged combination with encorafenib + binimetinib + cetuximab following encorafenib + cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer.

TPS271 Background: While the triplet combination of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CET) indicated higher response rate compared to the doublet combination of ENCO + CET, no significant survival benefits of the triplet combination were observed in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) according to BEACON CRC study. Although ENCO + CET is the standard 2nd-line therapy in the United States and European Union, poor prognoses are expected after disease progression. As resistant mechanisms of BRAF + EGFR blockage, several MAPK pathway alternations, including RAS and RAF mutations were reported, which suggests the additional blockade of MAPK signaling may be an effective strategy for ENCO + CET refractory mCRC. In addition, the preclinical study suggested BRAF inhibitor + anti-EGFR antibody resistant BRAF V600E-mutant colorectal cancer cell-lines were sensitive to the combination of BRAF inhibitor + MEK inhibitor + anti-EGFR antibody (Oddo D, et al. Cancer Res. 2016). Methods: BAYONET is a single-arm multicenter phase II trial to evaluate the efficacy and safety of the staged combination with ENCO + BINI + CET for patients with BRAF V600E-mutant mCRC who were refractory to ENCO + CET. The main eligibility criteria are as follows; RAS wild-type/ BRAF V600E-mutant mCRC; age ≥ 20; ECOG PS 0 or 1; within 4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO + CET; complete response, partial response, or ≥4 months of stable disease were observed in the previous ENCO + CET. Included patients receive the combination treatment of ENCO (300mg once a day) + BINI (45mg twice a day) + CET (400mg/m2 initial dose and then 250mg/m2 once a week) in a 28 day-cycle as a study treatment. The primary endpoint of this trial is 12-week progression-free survival (PFS) rate. The secondary endpoints include PFS, overall survival, objective response rate, disease control rate, time to treatment failure, and the incidence of adverse events. The targeted sample size was calculated to be 30 on the basis of a power of 80%, a significant level of 10% (one-sided), the threshold 12-week PFS rate of 20%, and the expected 12-week PFS rate of 40%. As a translational analysis, circulating tumor DNA for next-generation sequencing using Guardant360 is collected at twice time points (before and after study treatment) to investigate the resistance mechanisms. Enrollment started from Jan 2022 and is ongoing at 25 facilities in Japan. As of Sep 20, 2022, 9 patients were enrolled. Clinical trial information: jRCTs031210510 .

Durvalumab with or without tremelimumab in patients with persistent or recurrent endometrial cancer or endometrial carcinosarcoma: A randomized open-label phase 2 study

IntroductionOur understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear. MethodsWe conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%. ResultsEighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8–100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4–100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified. ConclusionsIn these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches.

Abstract PD4-06: Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study

Abstract Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p<0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p<0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [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 PD4-06.

Abstract OT2-19-06: Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL

Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [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 OT2-19-06.

A single‐arm, multicenter, open‐label phase 2 trial of surufatinib in patients with unresectable or metastatic biliary tract cancer

Several clinical studies of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) therapy as a second-line treatment for biliary tract cancer (BTC) have shown modest efficacy. In this study, surufatinib was evaluated as a second-line VEGFR therapy in patients with BTC. This was a single-arm, multicenter, open-label phase 2 study conducted in China. The study enrolled eligible patients with BTC, who had received surufatinib monotherapy as second-line treatment, at a dose of 300 mg, once daily, in 28-day cycles. Tumor assessments were performed every 8 weeks (±7 days) according to the Response Evaluation Criteria in Solid Tumors version 1.1. As of November 30, 2018, 39 patients with BTC, including 29 (74.4%) with intrahepatic cholangiocarcinoma, 5 (12.8%) with extrahepatic cholangiocarcinoma, and 5 (12.8%) with gallbladder cancer, were enrolled and treated with surufatinib. The 16-week progression-free survival rate was 46.33% (95% CI, 24.38-65.73), with median progression-free survival of 3.7 months and median overall survival of 6.9 months. In addition, results from subgroup and post hoc analyses revealed that patients with the proper tumor locations or appropriate levels of serum biomarkers might receive greater clinical benefits. The top 3 treatment-related adverse events with severity of grade ≥3 included blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). When applied in the treatment of patients with BTC, surufatinib monotherapy has offered moderate clinical efficacy and shown expected tolerability and safety profiles.

Anlotinib in the treatment of advanced hepatocellular carcinoma: an open-label phase II study (ALTER-0802 study)

PurposeThis study aimed to assess efficacy and safety of anlotinib as a first- or second-line treatment for advanced or metastatic hepatocellular carcinoma (aHCC) and to identify the predictive plasma cytokines on efficacy of anlotinib.MethodsIt was a phase II clinical study. Patients with aHCC were recruited from October 2016 to April 2019 and divided into two cohorts according to previous tyrosine kinase inhibitors (TKIs) therapy. Those without or with prior TKIs were in Cohort 1 or 2, respectively. All patients took anlotinib (12 mg/day, Day1–14, 3 weeks per cycle). The primary endpoint was 12-week progression-free survival (PFS) rate. Relationship between the series plasma cytokine level and the efficacy of anlotinib was analyzed.ResultsEnrolled 26 patients in Cohort 1 and 24 in Cohort 2. In Cohort 1, the 12-week PFS rate was 80.8% [95% confidence interval (CI); 59.8%–91.5%] and median time to progression (TTP) was 5.9 months (95% CI 4.8–6.9). In Cohort 2, the 12-week PFS rate and median TTP was 72.5% (95% CI 48.7%–86.6%) and 4.6 months (95% CI 2.7–10.0), respectively. The median TTP on patients with a baseline plasma level of CXCL1 (C-X-C motif chemokine ligand 1) less than 7.6 ng/μl was significantly longer in both cohorts. The most common grade 3–5 adverse events were hypertension (8%), diarrhea (8%) and hand-foot syndrome (6%).ConclusionAnlotinib showed promising efficacy and safety as a first- or second-line treatment with a continuous TKIs treatment strategy in aHCC. The plasma CXCL1 might be a predictor for the efficacy of anlotinib.

Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

BackgroundThis Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.MethodsEligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).ResultsIn Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).ConclusionsTepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.Trial RegistrationClinicalTrials.gov: NCT02115373.

OSTPDL1: A phase II study of avelumab, a monoclonal antibody targeting programmed death-ligand 1 (PD-L1) in adolescent and young adult patients with recurrent or progressive osteosarcoma.

10521 Background: Outcomes for recurrent osteosarcoma are poor and novel therapies are needed. Osteosarcoma has a high mutational burden with overexpression of PD-L1 in metastatic lesions, providing a rationale for testing immune checkpoint inhibitors in this population. We therefore evaluated the activity of the PD-L1 inhibitor avelumab in patients with recurrent or progressive osteosarcoma. Methods: We conducted a single-arm, open-label phase 2 trial at 4 collaborating institutions. Eligible subjects were ages 12 to ≤50 years with recurrent or progressive osteosarcoma and radiographic evidence of measurable disease. Subjects received avelumab 10 mg/kg intravenously every 2 weeks of 28-day cycles until disease progression or unacceptable toxicity. Primary endpoints were objective response rate (CR + PR according to RECIST v.1.1), and progression-free survival (PFS) at 16 weeks. Kaplan-Meier methods were used to estimate PFS. Secondary endpoints included toxicity. Correlative objectives included measurement of subsets of peripheral blood mononuclear cells and serum markers of immune activation, and measures of cell proliferation, co-inhibitory receptor expression on CD8 T cells, T cell repertoire, and epigenetic programming of T cells. Results: Between February 2017 and October 2019, 18 eligible subjects [67% male, median age 16.8 years (12.8-22.9)] were enrolled. Subjects had received median 3 prior systemic therapies (range 1-5). Sites of disease included lung/pleura (94%), bone (56%), and soft tissue (28%). Subjects received a median of 2 cycles (range 1-4) of avelumab. Median PFS was 8 weeks (95% CI 6.7-9.1). No objective responses occurred (17 with progressive disease), and the 16-week PFS was 0%. The most common adverse events (AEs) were alanine aminotransferase (ALT) elevation (17%), aspartate aminotransferase (AST) elevation, dyspnea, hyponatremia, and pain (each 11%). Treatment-related serious AEs (≥Grade 3) included dyspnea (n = 2), ALT/ALT elevation, hyponatremia, pericardial effusion and anemia (n = 1). Immune-related AEs included pneumonitis, Hashimoto thyroiditis, and pericardial effusion (all n = 1). One patient discontinued therapy after 1 dose due to grade 4 ischemic stroke, unrelated to avelumab. One death occurred on study due to rapid disease progression. Conclusions: Avelumab did not demonstrate activity in recurrent osteosarcoma. Correlative biology studies are ongoing to elucidate mechanisms of resistance to this therapy. Clinical trial information: NCT03006848.

Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.

5058 Background: Therapeutic options for patients with advanced germ cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. We aimed to evaluate olaparib activity in patients with refractory GCT. Methods: In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer IGG-02 study (NCT02533765), patient eligibility included failure after high-dose chemotherapy or after at least 2 different cisplatin-based regimens. Measurements of serum tumor markers and computed tomography were carried out at baseline and every 6 weeks of olaparib treatment. The study primary endpoint was the overall response rate, the study planned to recruit initially 18 patients and not continue further recruitment until one or more responses were observed. Results: Between September 2015 and February 2019, 18 patients, median age 39 years (range, 22-61) were enrolled. The number of prior chemotherapy regimens was: 2 for 3 patients (16.7%), 3 for 5 patients (27.8%), &gt;3 for 10 patients (55.6%). Sixteen cases (89.9%) received prior high-dose chemotherapy with support of hematopoietic progenitor cells. Grade 3-4 adverse events were observed in 5 patients (27.7%). There were no partial responses, 5 cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 7+ months and 13 (72.2%) progressive disease. The 12-week progression-free survival probability was 27.8% [95% confidence interval (CI): 10.1%-48.9%]. The 12-month overall survival probability was 27.8% (95% CI: 10.1%-48.9%). A germline DNA repair profile panel showed only a BRCA1 mutated case associated with a SD lasted 4 months. Conclusions: Olaparib as a single agent has marginal activity in heavily pretreated GCT patients, however, an anecdotic 4-month SD in the only BRCA mutated patient has been reported. Plans for future studies with olaparib are suggested in combination or following salvage chemotherapy in less pretreated and more selected GCT patients. The Study has been conducted with AstraZeneca contribution. Clinical trial information: NCT02533765 .

A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial.

Background:Prognosis of patients affected by metastatic esophageal–gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.Methods:The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib.Discussion:Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance.Protocol number:CRC2017_02EudraCT Number:2017-004522-14

Treatment of refractory germ-cell tumours with single-agent cabazitaxel: a German Testicular Cancer Study Group case series.

Outcomes of multiply relapsed, refractory germ-cell tumour (GCT) patients remain poor with an overall survival (OS) of a few months only. Thus, new therapeutic advances are urgently needed. Cabazitaxel has shown preclinical activity in platinum-resistant GCT models. Here, we report the first clinical case series of cabazitaxel treatment for platinum-refractory GCT. Data of multiply relapsed GCT patients receiving single-agent cabazitaxel were retrospectively analysed. Endpoints included 12-week progression-free survival (PFS) rate, disease control rate, tumour marker responses, median PFS and OS, and toxicity. Cabazitaxel showed limited activity in 13 heavily pre-treated GCT patients. After a median follow-up of 23weeks (IQR 29), 69% of patients were deceased. A median of 2 cycles of cabazitaxel (range 1-7) were applied. The 12-week PFS rate was 31%. Median PFS and OS were 7 and 23weeks, respectively. Two patients achieved objective responses (15%), three patients (23%) achieved a tumour marker decline ≥ 50%, and the disease control rate was 39%. Cabazitaxel was well tolerated. CTCAE° III-IV haemato-toxicity was most common (54%), and dose reductions were scarce (15%). In this case series, cabazitaxel showed limited activity in heavily pre-treated GCT patients. Two-phase II studies are underway (NCT02115165, NCT02478502) prospectively assessing cabazitaxel in multiply relapsed GCTs.

Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer

BackgroundA previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings.MethodsRecords of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution.ResultsTotally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3–5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8–2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48–0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444).ConclusionsIn real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities.Trial registrationRetrospectively registered.

Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer

ObjectivesKRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. Materials and methodsPatients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. ResultsFifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1–8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. ConclusionIn heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated.