Pretreated Patients Research Articles

Anti-tumor activity of sunvozertinib in NSCLC with EGFR sensitizing mutations after failure of EGFR TKI treatment.

9103 Background: Sunvozertinib is a rationally designed, irreversible EGFR inhibitor targeting various EGFR mutations with wild-type EGFR selectivity. Clinical studies have showed its superior efficacy than current available therapies and favorable safety profile for treating NSCLC patients with EGFR exon20 mutations. Here we reported its anti-tumor activity in patients with EGFR sensitizing mutations (EGFRm) who failed from standard EGFR TKI treatment. Methods: This is a pooled analysis of three clinical studies in patients with EGFRm or HER2m NSCLC: WU-KONG1 (multinational phase I/II study, NCT03974022), WU-KONG2 (phase I study in China, CTR20192097), and WU-KONG15 (phase II study in China, NCT05559645). Patients were enrolled to receive sunvozertinib once daily at defined doses until discontinuation criteria were met. Patients who had EGFRm NSCLC, at least one measurable lesion at baseline, received at least one dose of sunvozertinib, and underwent at least one post-treatment RECIST assessment were evaluable for efficacy analysis. Patients with EGFRm or HER2m NSCLC who failed from standard systemic therapies and received at least one dose of sunvoertinib were included in the safety analysis. Results: As of October 17, 2022, a total of 32 patients who met efficacy evaluable criteria were included in the analysis. The doses of sunvozertinib ranged from 50 mg - 400 mg. Baseline characteristics: median age was 64.5 years old; 68.8% (22/32) were female; 75.0% (24/32) ECOG PS was 1; 34.4% (11/32) had more than three metastatic sites; 43.8% (14/32) had baseline brain metastases. Patients were heavily pretreated, with a median of 5 lines (range 1 - 16) of prior therapies. All patients had been treated with at least one type of EGFR TKI, including 68.8% (22/32) had been treated with a 3rd generation EGFR TKI. The majority of patients (29/32, 90.6%) had also been treated with chemotherapy. Anti-tumor activity was observed starting from 50 mg. Per investigators’ assessment, the best objective response rate (BoR) was 21.9% (7/32). Anti-tumor activity was observed regardless of T790M mutation status. At the data cutoff date, the median duration of response and progression-free survival were 4.0 months and 5.9 months, respectively. Sunvozertinib was well-tolerated across all dose levels. The safety profile was similar to what has been previously reported. The longest treatment duration was more than 35 months (still ongoing). Conclusions: Sunvozertinib monotherapy demonstrated promising anti-tumor activity in heavily pretreated EGFRm NSCLC patients. Further clinical evaluation of sunvozertinib in this patient population is warranted. The updated data will be presented at the conference. Clinical trial information: NCT05559645 NCT03974022 and CTR20192097 .

Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy

BackgroundImmune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden...

Extracorporeal removal of soluble tumor necrosis factor receptors for the treatment of advanced refractory solid tumors.

e14593 Background: Tumor necrosis factor-alpha (TNF) has well-established anti-tumor effects including cytotoxicity against tumor vasculature. Past use of recombinant TNF to treat solid tumors resulted in unacceptable toxicities when given systemically but is successfully used in localized limb perfusion to treat melanoma and sarcomas. An alternative to promote endogenous TNF-mediated anticancer activity involves therapeutic apheresis to reduce the high concentrations of soluble TNF receptors (sTNF-Rs) produced by tumors, which sequester TNF and inhibit its tumoricidal effects. Methods: The LW-02 Column contains recombinant single-chain TNF, a capture ligand that selectively removes sTNF-Rs from plasma, covalently linked to a bead matrix. LW-02 Column Immunopheresis was evaluated in heavily pretreated patients with metastatic melanoma, renal cell carcinoma or triple negative breast cancer [NCT04142931]. LW-02 Column Immunopheresis was performed 3x/week, processing up to two plasma volumes for approximately 12 weeks as monotherapy (Cohort A, n = 6) or combined with nivolumab (Cohort B, n = 5). The study evaluated column performance, safety, clinical efficacy, and immunological biomarkers in the tumor microenvironment and blood. Results: The LW-02 Column effectively reduced sTNF-R plasma concentrations with capture efficiencies of 95.6% and 82.8% for sTNF-R1 and sTNF-R2, respectively, at the 30-minute procedural time point. At the data cut-off (Sept 30, 2022), median overall survival (OS) was 34.7 and 44.4 weeks for all patients (n = 11) and patients treated for ≥4 weeks (n = 8) (the latter group was prespecified in the protocol), respectively. For Cohorts A and B, median OS was 34.7 weeks and 45.4 weeks, respectively, for patients treated for ≥4 weeks. Evaluation of safety showed that only 2 adverse events (AEs) of 95 total AEs (including 7 SAEs) were deemed possibly related to LW-02 Column treatment. Immunohistochemical evaluation of tumor biopsies obtained 10-14 weeks after initiating LW-02 Column Immunopheresis revealed increased tumor-infiltrating lymphocytes (CD8+, HLA-DR+, and/or PD-1+ cells; 5/5 patients examined), and a reduced presence of tumor-associated macrophages (CD68+; 4/5 patients) compared to pretreatment biopsies. Preliminary immune profiling of peripheral blood mononuclear cells (5 patients) revealed increased expression levels of transmembrane TNF-R1 and TNF-R2, suggestive of increased cellular TNF responsiveness, and increased expression of activation molecules HLA-DR and CD86 after 4 weeks of LW-02 Column monotherapy compared to pretreatment levels. Conclusions: LW-02 Column Immunopheresis achieved safe and effective depletion of sTNF-Rs from plasma of patients with solid tumors. Further studies will assess the clinical benefit profile of the LW-02 Column for resensitizing tumors to respond to immunotherapy. Clinical trial information: NCT04142931 .

Combination of regorafenib with BRAF-/MEK-inhibitors for the treatment of patients with refractory melanoma brain metastases.

e14003 Background: there are no active treatment options available for patients (pts) diagnosed with melanoma brain metastases (MBM) that progress despite treatment with immune checkpoint inhibitors (ICI), and BRAF-/MEK-inhibitors (BRAF/MEKi) in pts with BRAF V600mutant melanoma. Regorafenib (REGO), an oral multi-target kinase inhibitor, including potent inhibition of RAF-dimers, has single-agent activity in pretreated melanoma (AS Vander Mijnsbrugge et al. SMR 2022). Here we report our single-institution experience with REGO in combination with BRAF/MEKi in pts with refractory MBM. Methods: pts were identified prospectively, medical records were reviewed retrospectively. Results: 13 pts with stage IV-M1d melanoma were included (6F, med age 54y [range 33-72], WHO PS: 0/1/2/3 resp. n = 1/4/6/2 pts, BRAF V600mut: n = 9, NRAS Q61mut: n = 4). Pts previously progressed on ICI (anti-PD-1 and -CTLA-4; 13 pts); BRAF-/MEK-inhibitor (all BRAF V600mut pts); chemotherapy (3 pts), T-VEC (2 pts), REGO mono (2 pts), and REGO+ICI (2 pts). At baseline, 11 pts had active MBM (8 pts on corticosteroids); 10 pts had extracranial evaluable disease. Pts were treated with REGO (40-80 mg QD) combined with BRAF/MEKi in 9 BRAF V600mut pts (dabrafenib/trametinib: n = 4; encorafenib/binimetinib: n = 5) or, in 4 NRAS Q61mut pts, with trametinib or binimetinib (+ low-dose BRAF-inhibitor if needed to mitigate skin toxicity). Treatment was stopped in 8 pts because of PD and is ongoing in 5 pts (3-49 wks after initiating therapy). There were no grade 4-5 TRAE. Grade 3 TRAE included: arterial hypertension (n = 4), hepatotoxicity (n = 2), diverticular bleeding (n = 1), and duodenal perforation, treated conservatively (n = 1). None of the 2 pts without active MBM at baseline progressed within the CNS. In 11 response evaluable pts (incl. 10 with evaluable extracranial metastases), best objective intracranial response (according to RANO-BM) was PR in 4 pts (36%; 3 BRAF V600mut pts), and SD in 4 pts (36%; 3 BRAF V600mut pts). Intracranial responses corresponded with extracranial responses in all but 3 pts (1 NRAS Q61mut pt with a PR intra-, had SD extracranially; 1 BRAF V600mut pt and 1 NRAS Q61mut pt with SD intra-, had PD extracranially); considering a potential clinical benefit of therapy beyond first PD, both pts continued treatment and remained clinically stable at the latest FU (resp. 15 and 49 wks after initiating therapy). Median time on REGO+BRAF/MEKi in BRAF V600mut pts was 15.9 wks (range 3-46), and on REGO+MEKi in NRAS Q61mut pts: 7.6 wks (range 3-49). Median PFS and OS: 12.9 and 26.4 wks (resp. 15.3 and 26.4 wks in BRAF V600mut pts; 8.6 and 10.1 wks in NRAS Q61mut pts). Conclusions: in heavily pretreated patients with MBM combination of REGO with BRAF-/MEK-inhibitors demonstrated promising anti-tumor activity. Further investigation of safety and clinical activity in a prospective trial is warranted.

Overall survival of patients with BRAF-mutant metastatic colorectal cancer treated with encorafenib-cetuximab in a real-world nationwide study in the Netherlands.

3589 Background: Approximately 10-15% of patients with metastatic colorectal cancer (mCRC) have BRAFV600E mutated tumors. Encorafenib plus cetuximab (EC) combination treatment was approved following the results of the randomized phase III BEACON trial and is currently recommended for all pretreated patients with BRAFV600E-mutant mCRC. Selection of patients in randomized controlled trials is based on restrictive eligibility criteria and often not representative of the patient population in daily clinical practice. Complementary real-world effectiveness studies can improve knowledge on the generalizability of trial results, and support decision making in clinical practice. Methods: This population-based study included all mCRC patients in the Netherlands treated with EC since approval in October 2020 until June 2022. Individual patient data and original pathology reports were collected. Primary endpoint was overall survival (OS), defined as time from EC initiation until death by any cause, analyzed by Kaplan-Meier curves. WebPlotDigitizer was used to reconstruct the Kaplan-Meier survival curve of the BEACON trial. Uni- and multivariable analyses were performed. Subgroup analyses were conducted for patients who would have been eligible for the BEACON trial based on key eligibility criteria: BRAFV600E mutation, 1-2 prior regimens, world health organization performance status (WHO PS) of 0-1, normal neutrophil count, absence of brain metastases, no prior RAS/RAF/MEK treatment, and no concurrent malignancies. Results: 155 patients were included with a median follow-up time of 11.1 months. Patient characteristics differed from BEACON in mean age (64 versus 60 years), primary tumor sidedness (69% versus 50% right-sided) and WHO PS (23% versus 51% WHO 0). Median OS of the total real-world cohort was 6.6 months (95% CI: 6.0-8.3) and differed significantly from BEACON (9.3 months; 95% CI: 8.0-11.3; p = 0.003). 35% of real-world patients treated with EC would not have been eligible for the BEACON trial, showing an inferior median OS of 6.0 months (95% CI: 4.6-9.2) compared to 7.0 months (95% CI: 6.4-9.8) in trial eligible real-world patients. WHO PS was independently associated with poor survival in multivariable analysis. Patients with WHO PS≥2 had a median OS of 3.9 months (95% CI: 2.4-NA) with a hazard rate of 2.5 (95% CI: 1.1-5.5; p = 0.003). Conclusions: This largest to date - unselected - population-based cohort of mCRC patients treated with EC showed an efficacy-effectiveness gap for OS. These outcomes should be considered in clinical practice for treatment decision making. Omitting EC for subgroups demonstrating very short OS, such as patients with WHO PS ≥2, needs to be considered. Further research is warranted to adapt treatment guidelines towards a more personalized approach for patients with BRAFV600E-mutated mCRC.

A prospective, single-arm, single-center, exploratory clinical study of anlotinib combined with irinotecan in second-line and above treatment of HER-2–negative advanced breast cancer.

e13114 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Irinotecan is a semi-synthetic water-soluble camptothecin derivative which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of irinotecan combined with anlotinib in second-line and above treatment of HER-2 negative advanced breast cancer. (ChiCTR2000037448) Methods: This open-label, single-arm, phase II study enrolled women aged 18 years and older with HER2-negative breast cancer who underwent ≥1 line chemotherapy, All patients were treated with irinotecan (60mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to November 2022, 14 patients were enrolled in this study. Median follow-up was 10.8 months (95% CI 4.3-17.3). Median PFS was 5.9 months (95% CI 2.0-9.8). Of all the patients whose efficacy could be evaluated (13/14), no patient achieved complete response (CR); 3(23.07%) and 8(61.54%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 23.1% (95% CI 5.0-53.8) and DCR was 84.6% (95% CI 54.6-98.1). OS has not reached. The major treatment-related adverse events (incidence≥10%) were fatigue (42.86%), hypertension (42.86%), neutropenia (28.57%), hand foot syndrome (21.43%) and myelosuppression (14.29%). There is no grade 3/4 adverse events occurred.28.57% (4/14) of patients had dose reductions. Conclusions: The combination of irinotecan and anlotinib showed better treatment response and tolerable toxicity in the treatment of second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed. Clinical trial information: ChiCTR2000037448 .

CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma.

8009 Background: Heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months (mo). In the single-arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), pts received a single infusion of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting BCMA. At the final protocol-specified analysis (27.7-mo median follow-up [MFU]), overall response rate (ORR) was 98%, with 83% stringent complete response (CR); 27-mo rates of progression-free survival (PFS) and OS were 55% and 70%, respectively. Here, we report study closeout results. Methods: Eligible pts received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD) negativity at 10-5. Results: 97 pts received cilta-cel (median age 61 years [y]; median 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, MFU was 33.4 mo (range, 1.5-45.2). Median (m) duration of response was 33.9 mo (95% CI, 25.5–not estimable [NE]). mPFS was 34.9 mo (95% CI, 25.2–NE), with an estimated 47.5% progression free and alive at 36 mo. mOS was not reached (NR), with an estimated 62.9% survival at 36 mo. Of 49 MRD-evaluable pts, 26 had MRD negativity sustained for ≥12 mo, of which 20 had sustained MRD-negative ≥CR. mPFS was NR in these subgroups (Table). 18 pts were MRD negative with ≥CR at 24 mo post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-mo MFU. 6 new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta-cel]), for a total of 35 (PD, n=17; unrelated to cilta-cel, n=12; related, n=6). Conclusions: Longer mPFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated pts with RRMM. Achieving CR and/or sustained MRD negativity was associated with prolonged PFS. Pts continue to be followed for safety and survival in the 15-y CARTINUE long-term study (NCT05201781; MMY4002). Clinical trial information: NCT03548207 . [Table: see text]

Initial results from a first-in-human, phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors.

2502 Background: AhR activation is involved in tumor growth, immunomodulation, and resistance to immune checkpoint inhibitors. BAY2416964 is a novel, potent, oral AhR inhibitor (AhRi) that antagonizes AhR ligand-induced immunosuppressive effects, resulting in enhanced proinflammatory activity of antigen-presenting cells and T cells and reduced activity of immunosuppressive myeloid cells. Methods: A first-in-human, Phase I clinical trial of AhRi BAY2416964 (NCT04069026) is evaluating its safety, pharmacokinetics, pharmacodynamics, recommended Phase II dose, and anti-tumor activity per RECIST v1.1 and iRECIST. BAY2416964 was administered orally in patients with advanced solid tumors in a dose-escalation cohort using a modified toxicity probability interval (mTPI) design. The initial expansion cohorts enrolled patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Results: As of November 4, 2022, 72 patients had been treated with BAY2416964: 39 patients in dose escalation and 33 patients in the initial dose expansion treated with 500 mg twice daily (25 NSCLC, 8 HNSCC). The most common tumor types enrolled in dose escalation were colorectal cancer ( n= 12), breast cancer ( n= 6), and pancreatic cancer ( n= 4). Median age was 61 years (range 35-80). 51/72 (70.8%) patients had received ≥3 lines of therapy (including 16 [22.2%] who had received ≥6 lines) and 47/72 (65.3%) had received immune checkpoint inhibitors. Drug-related treatment-emergent adverse events (TEAEs) of all grades reported in ≥10% of patients were nausea (13.9%; 1.4% grade 3) and fatigue (11.1%; 1.4% grade 3). Most drug-related TEAEs were grade 1 or 2; 9 (12.5%) patients experienced drug-related grade 3 TEAEs and no patients experienced drug-related grade ≥4 TEAEs. No dose-limiting toxicities were observed. Two patients in dose expansion discontinued treatment due to drug-related TEAEs. Plasma exposure to BAY2416964 increased according to dose and food intake. Analysis of biomarkers demonstrated evidence of target engagement and an increase in immune activation at the doses tested. Of 67 patients evaluable for response by RECIST, 22 (32.8%) had stable disease per RECIST v1.1, including 1 with thymoma in dose escalation achieving an iRECIST partial response. Conclusions: BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients. The disease-specific dose-expansion part of this study is ongoing. The observed manageable safety profile also supports combination therapies. Clinical trial information: NCT04069026 .

Clinical validity of oncogenic driver genes detected from circulating tumor DNA in the blood of lung cancer patients.

This study aimed to evaluate the concordance of oncogenic driver mutations between tumor tissues and circulating tumor DNA (ctDNA) in patients with lung cancer. In addition, this study attempted to reveal the clinical utility of ctDNA in lung cancer treatment. Recurrent or metastatic non-small cell lung cancer (NSCLC) patients were prospectively enrolled in this study. Tumor tissue and serial blood samples were obtained from newly diagnosed patients (Cohort A) or patients treated with targeted therapy (Cohort B) and targeted gene panel sequencing was conducted to identify tumor mutational profiles. At the time of diagnosis, patients in Cohort A with a high cell-free DNA (cfDNA) concentration had poorer overall survival than those with a low cfDNA concentration. The sensitivity and precision of ctDNA analysis in pre-treatment patients compared with those of tissue sequencing were 58.4% and 61.5%, respectively. Known lung cancer-associated variants of oncogenic driver genes, including EGFR and KRAS, and tumor suppressor genes, including TP53 and APC, were frequently detected in the ctDNA of the patients (76.9%). An association between smoking and TP53 mutation status was observed in both tissues and ctDNA (P=0.005 and 0.037, respectively). In addition, the EGFR T790M resistance mutation was detected solely from the ctDNA of two patients after treatment with an EGFR tyrosine kinase inhibitor. ctDNA may be a reliable prognostic biomarker with an additional role in treating patients with lung cancer. Further analyses are necessary to understand the properties of ctDNA and widen its clinical use.

AFM13 IN PATIENTS WITH CD30 POSITIVE RELAPSED OR REFRACTORY (R/R) PERIPHERAL T CELL LYMPHOMA (PTCL): RESULTS FROM THE PHASE 2 REDIRECT STUDY

Introduction: PTCLs are aggressive hematologic malignancies often with poor prognoses; there is no standard of care therapy for patients with R/R PTCL. AFM13, a tetravalent, bispecific innate cell engager, binds CD30 when expressed on PTCL cells, and CD16A on innate effector cells, augmenting the innate immune response to CD30+ tumor cells. Phase 1 clinical trials of AFM13 in patients with R/R Hodgkin lymphoma (HL) and cutaneous CD30+lymphomas showed a tolerable safety profile and clinical activity; correlative science data in a small group of AFM13-responsive patients with HL showed increased natural killer (NK) cell activity. Methods: A Phase 2 study (NCT04101331) assessed the efficacy of AFM13 in patients with select R/R PTCL subtypes, exhibiting histologically confirmed CD30+expression in ≥1% tumor cells, who had received ≥1 prior systemic therapy. The primary endpoint was to assess the overall response rate (ORR) by FDG-PET per independent review committee. Secondary endpoints included safety, complete response rate (CRR), and duration of response (DoR). Progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. Patients received 200 mg AFM13 intravenously once weekly until disease progression, intolerable toxicity, consent withdrawal or termination by the investigator. Results: Patients (n = 108; age 21–93; 61% male) received AFM13 with a median (min, max) number of infusions of 9.0 (1, 116). PTCL subtypes assessed (n) were: PTCL not-otherwise-specified (PTCL-NOS, 41); angioimmunoblastic T cell lymphoma (AITL, 30); anaplastic large cell lymphoma (ALCL, 26); other (11). Patients had received a mean of 2.7 prior treatment lines; 46.3% received prior brentuximab vedotin (BV), 17.6% received prior auto-transplant. The ORR was 32.4% (CRR was 10.2%); ORR per subtype was 22.0% (PTCL-NOS), 53.3% (AITL), 23.1% (ALCL), and 36.4% (other). Median DoR, PFS, and OS were 2.3 months, 3.5 months, and 13.8 months, respectively. AFM13-related treatment emergent adverse events (TEAEs) occurred in 79/108 patients (73.1%); 14 events in 9 patients (8.0%) were considered serious. The most frequent TEAE was infusion-related reactions, as reported by the investigator, seen in 34/108 patients (31.5%), including 12 Grade 3 events in 6 patients (5.7%). Neutropenia was the most frequent Grade ≥3 TEAE occurring in 9.3% of patients. Conclusion: AFM13 monotherapy demonstrated robust clinical activity in heavily pretreated patients with R/R PTCL. The safety profile of AFM13 was well managed and consistent with previously reported data from prior and ongoing clinical studies with AFM13. These data support future evaluation of AFM13 in combination with other immunotherapies, including allogeneic NK cells, to further potentiate anti-tumor immune responses to CD30+ lymphomas. Keyword: immunotherapy Encore Abstract—previously submitted to AACR 2023 The research was funded by: Affimed GmbH Conflicts of interests pertinent to the abstract W. S. Kim Research funding: Sanofi; BeiGene; Boryung; Roche; Kyowa Kirin Co., Ltd.; Dong-A Pharmaceutical Co., Ltd. J. Shortt Consultant or advisory role: Bristol Myers Squibb; Novartis; Otsuka; Astellis; Mundipharma; Pfizer Research funding: Astex; Amgen; Bristol Myers Squibb; Novartis P. L. Zinzani Consultant or advisory role: MSD; Eusapharma; Novartis; Celltrion Healthcare; Gilead; Janssen-Cilag; Bristol Myers Squibb; Servier; AstraZeneca; Takeda; Roche; Kyowa Kirin; Incyte; BeiGene; Secura Bio; Sandoz; ADC Therapeutics A. Marin-Niebla Other remuneration: Janssen; Gilead-Kite; Roche; Eli Lilly; Takeda; Kiowa-Kirin; AbbVie; AstraZeneca; BeiGene K. Alexis Employment or leadership position: Affimed Inc. Stock ownership: Affimed Inc. M. Emig Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH L. Garcia Employment or leadership position: Affimed Inc. Stock ownership: Affimed Inc. A. Overesch Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH K. Pietzko Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH S. Horwitz Consultant or advisory role: Affimed; Daiichi Sankyo; Kyowa Kirin; ONO Pharmaceuticals; SecuraBio; Takeda; Shoreline Pharmaceuticals; Yingli Pharma; Abcuro Inc. Tublulis GmbH Research funding: ADC Therapeutics; Auxilius Pharma; Celgene; CRISPR Therapeutics; Millennium/Takeda; Seattle Genetics; C4 Therapeutics; Verastem/SecuraBio

Expanding the spectrum of neoplasms harboring EWSR1:CREM fusion as detected by a real-world clinical genomics platform.

e15061 Background: Malignancies with various well-defined phenotypes and prognoses have been shown to possess gene fusions between Ewing Sarcoma Breakpoint Region 1 ( EWSR1) and one of the CREB family genes, specifically CREB1 and ATF1. However, less is known about neoplasms that harbor EWSR1:CREM rearrangements, which are thought to result in constitutive activation of CREM and subsequent dysregulation of oncogenes, such as BCL-2 family genes, EGFR1, and cyclins. EWSR1:CREM fusion has been identified in rare cases of angiomatoid fibrous histiocytoma, clear cell sarcoma, hyalinizing clear cell carcinoma of the head and neck, and intracranial myxoid mesenchymal tumor. Our study represents the largest to date and seeks to expand and further define the diversity of tumor subtypes that possess EWSR1:CREM fusions. Methods: Detection of EWSR1:CREM rearrangements by whole transcriptome sequencing was performed for > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ). Histological review of the identified tumors was performed by two board-certified pathologists (MGE, AER). Treatment and outcome information were collected, where available. Results: An EWSR1:CREM fusion was detected in 18 cases, which included one intracranial myxoid mesenchymal tumor, one mesothelioma, four hyalinizing clear cell carcinomas of the head and neck, two clear cell sarcomas, two small round and spindle cell sarcomas, and eight histologically malignant tumors having an epithelioid morphology. While the latter were in keeping with a disease entity recently reported in the medical literature (epithelioid neoplasm with predilection for mesothelial-lined cavities), several of these cases demonstrated unexpected neuroendocrine differentiation and were found at unusual sites, including the kidney, uterus, and cervical spine. Moreover, three cases had the features of squamous cell carcinoma. Surgical resection was performed in all patients, and pazopanib was utilized in two round and spindle cell sarcoma cases. This medication was shown radiographically to produce a partial response at 19 months and stable disease at 26 months, respectively, in heavily pretreated patients. Conclusions: By detecting an EWSR1:CREM rearrangement, molecular testing may aid in the diagnosis of a variety of rare tumor types, including a poorly understood malignant epithelioid neoplasm that arises in a variety of anatomic sites including mesothelial-lined cavities. Tumors harboring this fusion may ultimately be susceptible to treatment with tyrosine kinase inhibitor targeted therapy.

Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer.

e21162 Background: Immune checkpoint inhibitors (ICI) transformed non-small cell lung cancer (NSCLC) prognosis but response rate remains disappointing. Besides PDL1 expression, tumor mutational burden, quantification of tumor infiltrating lymphocytes or methylation profile failed to confirm their predictive role. The ICR (Immunologic Constant of Rejection) signature is defined as an immune phenotype quantifying the expression of 20 genes all involved in cancer immunity. Our first objective was the assessment of ICR signature predictive value and our secondary objectives were to compare ICR signature with other published immune signatures and to assess the prognostic value of ICR signature. Methods: Our series included 77 paraffin-embedded (FFPE) tumors derived from NSCLC patients treated with ICI as a single agent in at least the second line setting. We also collected clinical and biological data from 4 public data sets to expand and confront our local data. Transcriptomic analysis was performed using nCountertechnology Dx analysis by Nanostring based on microscopic imaging counting relative abundance of hundreds of transcripts using the “nCounter PanCancer Immune Profiling Panel” including the 20 ICR genes. Results: We applied the ICR classification to a series of 44 local tumor samples enhanced with 118 samples from public datasets. Hierarchical clustering on both local cohort and public datasets allowed us to distinguish the four ICR classes, from ICR 1 (“cold” tumors) to ICR 4 (“hot” tumors). Among the 5 datasets, we did not observe any significant difference between ICR groups for age, sex and smoking status. We observed a relative homogeneity in Durable Clinical Benefit (DCB) rate among ICR groups 2 to 4 (median DCB above 20%) unlike ICR group 1 (median DCB under 10%) leading us to consider ICR as a binary signature (ICR 1 vs ICR 2-4). ICR signature indeed showed a significant association with DCB among the 5 pooled datasets (OR = 4.40 [95% Confidence Interval 1.44-13.45] p = 0.950) with uniform distribution between them. Then, we conducted a logistic regression univariate analysis of DCB among various previously published immune signatures and ICR signature was the only one to show a significant association with DCB in this analysis ( p = 0.007). Conclusions: We identified a feasible transcriptomic signature with a promising signal of ICI efficacy prediction in the so far disappointing immune biomarkers field. In a near future, predict ICI efficacy will be a major challenge with three pivotal questions. When, balanced with the new data on ICI use in early-stage lung cancer or widely pretreated patients. How, assessing various techniques to develop composite signatures to better consider every driver of immune response. What, considering the amount of potential new therapeutic targets, starting by the 20 genes of ICR signature.

TACTIVE-U: Phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer.

TPS1121 Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), progression free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127 , NCT05573555 .

VERITAC-2: A global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.

TPS1122 Background: ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Methods: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N~560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation sub-population. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Clinical trial information: NCT05654623 .

Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.

The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.

e17509 Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.

Real-life experience of trastuzumab deruxtecan (T-DXd) in patients with heavily pretreated HER2 positive advanced breast cancer: A retrospective single institution study.

e13035 Background: T-DXd is a HER2 antibody–drug conjugate. It improves patient outcomes and is FDA approved for the treatment of patients with Her-2 positive and Her-2 low metastatic breast cancer. However, the impact of T-DXd use in real life compared with the findings reported in clinical trials with strict inclusion criteria has rarely been assessed. We performed a real-world study to evaluate the outcomes of patients with advanced HER2+ and HER2-low expression breast cancer. Methods: We conducted a retrospective single institution study and collected the clinical and pathologic data of patients with metastatic breast cancer who were treated with T-DXd from 2019 to 2022. The primary end point, time to treatment failure (TTF) was defined as the interval from T-DXd initiation to discontinuation. We compared the TTF of T-DXd with previous lines of treatment and also report its safety and tolerability. Results: Thirty-one patients were included in this study, seventeen with HER2-low expression and fourteen with HER2 positive. Patients had received a mean of three prior lines of therapy (ranging from 1 to 13). 32.2% of patients had ≥ 5 lines of therapy prior to T-DXd. TTF was 104 days, 95% CI [58,162] in T-DXd compared with 151 days, 95% CI [119,217] in the previous line of therapy. 2 patients (6.4%) had treatment discontinuation due to adverse events (AEs) (1 patient due to grade 3 fatigue and 1 patient due to concern for ILD). 3 patients (9.6%) had treatment delay or dose reduction due to AEs. A total of 67.7% of patients (21/31) developed AEs on T-DXd. 4 (12.9%) had grade 3 or 4 AEs. Fatigue was the most common AE followed by nausea/vomiting and thrombocytopenia. A total of 17 patients had T-DXd discontinued-15 patients discontinued due to progression or death, 2 discontinued due to AEs. 9 out of 31 patients had brain metastasis. Amongst patients with brain metastases, 7 showed stable disease while on T-DXd (1 had previously progressed on tucatinib, trastuzumab, and capecitabine). In the subgroup analysis, in patients with HER2-low expression, TTF was 98 days 95% CI [41-153] with T-DXd compared with 192 days, 95% CI [84,363] in the previous line of therapy. 2 out of 14 patients developed grade 3 or 4 AEs. Fatigue was the most common AE. In HER2+ subgroups, TTF was 126 days, 95% CI [58,353] in T-DXd vs 125 days, 95% CI [106,217] in the previous line of therapy. 2 out of 17 patients developed grade 3 or 4 AEs. Conclusions: To the best of our knowledge this is the first real life retrospective study evaluating the efficacy and tolerability of T-DXd. Overall, T-DXd had acceptable efficacy and tolerable toxicity in heavily pretreated patients. T-DXd showed a good response rate in patients with active brain metastasis. Our findings are consistent with published data on T-Dxd but is limited by virtue of retrospective series.

Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).

2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage > 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .

Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer: A multi-center, open-label, single-arm, phase II study.

e13102 Background: Eribulin is a non-taxane microtubule inhibitor approved in China for the treatment of patients with advanced breast cancer who progress after ≥2 lines of chemotherapy. Eribulin was shown to improve overall survival (OS) in various subgroups of patients with metastatic breast cancer (MBC) who were pretreated with an anthracycline and taxane. Furthermore, combination chemotherapy with eribulin plus gemcitabine led to a similar progression free-survival (PFS) benefit, with less neurotoxicity, as paclitaxel plus gemcitabine in patients with MBC who had not received prior cytotoxic chemotherapy for metastatic disease. However, the effect of eribulin plus gemcitabine on PFS in second-line or beyond remain unclear. Methods: This phase II, open-label, single-arm study was conducted at 13 institutions in China (NCT05263882). Patients with histologically confirmed HER2-negative MBC who had received at ≥1 prior taxane-containing chemotherapeutic regimen for advanced disease and had received anthracycline-containing regimens in the adjuvant setting, were enrolled between Nov 2021 and Oct 2022. Eligible patients received eribulin 1.4 mg/m2 and gemcitabine 1.0 g/m2 intravenously on days 1 and 8 of a 21-day cycle. Efficacy outcomes included PFS, objective response rate (ORR), and disease control rate (DCR), evaluated using RECIST v1.1. Adverse events (AEs) were graded according to The National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. Results: In total, 54 patients were included; 39 (72.2 %) were HR+/HER2- and 15 (27.8 %) were triple negative, the median age was 49.5 years (range: 31-70) and sites of metastasis were the liver (57.4%), lung (37.0%), bone (59.3%), brain (11.1%) and lymph nodes (53.7%). The median number of previous chemotherapy lines was 3 (range: 2-7): eribulin plus gemcitabine was used in second-line for 15 (27.8%) patients, third-line for 20 (37.0%) patients, fourth-line for 7 (13.0%) patients and ≥fifth-line in 12 (22.2%) patients. The median PFS was 7.7 months. The ORR was 40.7% and the DCR was 66.7%. Best overall responses and PFS rates at 3 and 6 months are shown. The most common grade 3-4 AEs were hematological: Leukopenia (35.2%), anemia (18.6%) and thrombocytopenia (9.4%). No treatment-related death was reported. Conclusions: Eribulin plus gemcitabine is effective in heavily pretreated patients with HER2-negative MBC with a predictable, manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

BackgroundImmune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are...