Prior Regimens Research Articles

Abstract 6427: Phase II study of trametinib alone and in combination with uprosertib in patients with metastatic triple negative breast cancer previously treated with chemotherapy: OSU 13317

Abstract Introduction: Triple negative breast cancers (TNBCs) are a poor prognosis subset of breast cancer and preclinical data implicate activation of the RAS/MEK/ERK pathway in TNBC chemotherapy resistance. Preclinical data demonstrate that blockade of both RAS/MEK/ERK and PI3K/AKT pathways synergizes to overcome resistance to single agent MEK inhibitors. The purpose of this study was to determine the response rate for the selective allosteric MEK1/MEK2 inhibitor trametinib alone and in combination with AKT inhibitor uprosertib in patients with metastatic TNBC previously treated with chemotherapy. Patients and Methods: This was an open-label, two-part, phase II, single-arm, multicenter study through the ETCTN. Eligibility criteria included patients with metastatic TNBC with measurable disease who had received between 1-3 prior chemotherapy regimens. All patients underwent a mandatory pretreament biopsy and received trametinib alone (2mg) as Part I of the study. At progression, patients underwent a second biopsy and moved to Part II with trametinib (1.5mg) and uprosertib (50mg). Available biopsies were profiled quantitative targeted absolute proteomics (QTAP) for kinome assay and whole transcriptome profiling via microarray. Blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and at progression for circulating tumor DNA (ctDNA) analysis via ultra-low pass whole genome sequencing. Results: Between October 2013 and January 2017, 37 patients were enrolled at 8 centers and, subsequently, 19 of these patients entered Part II. Adverse event data has been previously presented. On trametinib alone (Part I), 2 patients had a partial response (PR) and 6 patients had stable disease (SD) as best response. Of the 19 evaluable patients on trametinib + uprosertib (Part II), 3 patients had a PR and 3 patients had SD. Integrated analysis of matched samples with QTAP kinome and transcriptome data QTAP kinome assay in demonstrated MEK1/2 inhibition at progression on trametinib alone in 4/4 patients with evaluable tissue confirming target engagement and one patient with biopsy after trametinib+uprosertib demonstrated AKT1 inhibition. ctDNA was evaluable in 34 patients at C1D1 with tumor fraction (TFx) range 0-75.9%. 6/23 patients had ctDNA ‘clearance’ (tumor fraction of 0%) at C2D1. Of these 6, 3 (50%) had PR as best response, compared with only PR in only 1/17 patients without ctDNA clearance at C2D1. Conclusions: Trametinib alone and in combination with uprosertib demonstrates anti-tumor activity in a subset of TNBC patients with kinome evidence of target engagment. ctDNA clearance at C2D1 may be useful as an early biomarker to identify patients most likely to respond. Understanding biomarkers of response and resistance may guide future opportunities for MEK/AKT inhibition in TNBC. Citation Format: Vishnu Prasath, Hinda Boutrid, Ewa Mrozek, Maryam Lustberg, Robert Weslowski, Rachel Layman, Mahmoud Abdel-Rasoul, Cynthia Timmers, Erin MacRae, G. Thomas Budd, Lyndsay Harris, Claudine Isaacs, Roohi Ismail-Khan, Elizabeth Claire Dees, Andrew S. Poklepovic, Helen X. Chen, Miguel Villalona-Calero, William Carson, Gary L. Johnson, Daniel G. Stover, Bhuvaneswari Ramaswamy. Phase II study of trametinib alone and in combination with uprosertib in patients with metastatic triple negative breast cancer previously treated with chemotherapy: OSU 13317 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6427.

Trifluridine-Tipiracil (Lonsurf)


 CADTH recommends that Lonsurf be reimbursed by public drug plans in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in adults who have been previously treated with or are not candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti–vascular endothelial growth factor (anti-VEGF) biological agents; and, if positive for RAS wild-type disease, anti-epidermal growth factor receptor (anti-EGFR) agents, if certain conditions are met.
 Lonsurf should be covered for use in adults with histologically confirmed adenocarcinoma that cannot be surgically removed or has spread to other parts of the body and if the patient’s disease progressed or the patient was intolerant to a maximum of 2 prior chemotherapy regimens. Eligible patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system (CNS) or need increasing doses of steroids to control CNS disease.
 Lonsurf should be reimbursed in combination with bevacizumab. It should be prescribed by doctors who specialize in diagnosing and treating patients with mCRC. Lonsurf plus bevacizumab should be stopped if the disease worsens or the patient has severe side effects. The cost of Lonsurf should be reduced.

Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAFV600E-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program

BackgroundThe phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. Materials and MethodsThe EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. ResultsAmong the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. ConclusionThe efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.

Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial

In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRASG12 mutational status on OS in SUNLIGHT. In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRASG12 mutation versus those with a non-KRASG12RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). The presence of a KRASG12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRASG12 status.

Abstract A018: A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer

Abstract Introduction/Objective: This trial in progress is designed to evaluate the anti-tumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative treatment options, particularly for advanced or recurrent EEC remain necessary. Dysregulation of mammalian target of rapamycin (mTOR) signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EC. nab-Sirolimus, a nanoparticle injectable form of mTORi, is approved in the USA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that nab-sirolimus in combination with letrozole may produce synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemo-based regimen, Eastern Cooperative Oncology Group performance status score 0 or 1, naïve to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. The relationship between biomarkers and response outcomes is an exploratory endpoint. Citation Format: Lauren E. Dockery, Anna Priebe, Linda Duska, Angela K. Green, Cara Mathews, Fernanda Musa, David O'Malley, Allison Puechl, Li Ding, Anita N. Schmid, Willis H. Navarro, Brian Slomovitz, Kathleen Moore. A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A018.

Sacituzumab Govitecan (Trodelvy)


 CADTH recommends that Trodelvy should be reimbursed by public drug plans for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+, or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting, if certain conditions are met.
 Trodelvy should only be covered to treat adult patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have been previously treated with at least 1 taxane, at least 1 prior anticancer hormonal treatment, and at least 1 cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in any setting, have experienced treatment failure after 2 to 4 prior systemic chemotherapy regimens for metastatic disease, and have good performance status.
 Trodelvy should only be reimbursed if it is prescribed by clinicians with expertise and experience in treating breast cancer in approved centres, and if the price of Trodelvy is reduced.

Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032)

BackgroundPancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without...

Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.

603 Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]

A phase 2 study of the combination dostarlimab with niraparib in patients with penile carcinoma that has progressed following chemotherapy.

TPS13 Background: Penile squamous cell carcinoma (PSCC) is a rare and deadly cancer, with limited therapy options in patients with disease progressive on platinum chemotherapy. Patients are encouraged to enroll in clinical trials since the overall survival is less than 5 months with standard therapy. Development of efficacious treatment options for patients with chemotherapy refractory PSCC, remains an unmet need. Preclinical work suggests synergic activity between PARP inhibitors and immune checkpoint inhibitors in PSCC animal models. The niraparib plus dostarlimab combination may generate a robust antitumor immune response in cisplatin refractory patients with PSCC. Methods: This is an open-label, multi-center, Simon 2 stage design, phase 2 study to evaluate the efficacy and safety of the combination of niraparib and dostarlimab in patients with advanced relapsed/refractory PSCC. Patients must provide a sufficient tumor tissue sample for molecular and immune testing at screening. Blood samples will be collected at C1D1 for exploratory molecular testing, at C3D1 and at the time of investigator-assessed partial response (PR) or complete response (CR), and at the end of treatment visit. Niraparib at 200 mg daily will be administered orally once daily on days 1 to 21 and dostarlimab intravenously once every three weeks for cycles 1 to 4 and once every 6 weeks thereafter. Niraparib will be administered at 200 mg, oral, once daily, from days 1 through 21 until progression of disease or toxicity. Eligible patients must have histologically confirmed stage III (unresectable) or stage IV penile cancer according to the American Joint Committee on Cancer (AJCC) staging system, have had progression of disease or poor tolerance to one line of platinum therapy, have a life expectancy of more than 12 weeks, have an ECOG PS of 0 or 1 (ECOG PS 2 can be included after discussion with PI), measurable disease per Immune-Modified Response Evaluation Criteria in Solid Tumors iRECIST, adequate organ function, and must not have received any prior immuno-oncology regimens, cancer vaccines, adoptive cell therapies, or other cytokine therapies. The primary efficacy endpoint is Investigator-assessed confirmed overall response rate (ORR). Tumor response will be evaluated using iRECIST. Patients who receive at least 1 complete dose of either study drug will be considered evaluable for response. The secondary endpoints are to estimate the progression free survival (PFS) overall survival measured duration of Response (DOR) and to evaluate the safety and tolerability of the niraparib and dostarlimab combination in patients with PSCC. Six patients of the 25-patient target enrollment have been enrolled. Clinical trial information: NCT05526989 .

Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T.

LBA360 Background: NIVO IV has improved outcomes in multiple tumor types. Evolving treatment paradigms have created a need for administration options that address treatment burden and improve efficiencies of healthcare systems. SC delivery of antibodies for various cancer indications has proved safe and effective. CheckMate 67T (NCT04810078) is a multicenter, randomized, open-label, phase 3 study that evaluated PK and objective response rate (ORR) noninferiority of NIVO SC vs IV in patients (pts) with locally advanced or metastatic ccRCC. Methods: Enrolled pts had measurable disease that progressed during or after 1–2 prior systemic regimens, no prior immuno-oncology treatment, and a Karnofsky performance score ≥ 70. Pts were randomized 1:1 to receive NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3 mg/kg Q2W until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years’ treatment, or death. The co-primary PK endpoints for noninferiority testing were time-averaged serum concentration over the first 28 days (Cavgd28) and minimum serum concentration at steady state (Cminss) determined by a population PK analysis. ORR by blinded independent central review (BICR) was a key powered secondary endpoint for noninferiority testing. Other secondary objectives included additional PK exposure measures, safety, efficacy, and immunogenicity. Results: A total of 495 pts were randomized to NIVO SC (n = 248) or NIVO IV (n = 247). The median age was 64/66 years in the SC/IV arms. Most pts were male. Average injection time with NIVO SC was < 5 minutes. Noninferiority for the co-primary PK and key powered secondary ORR endpoints was met (see table). Incidence of NIVO SC local injection-site reactions was 8.1%; reactions were low grade and transient. Most deaths were due to disease progression; study drug toxicity led to 3/1 deaths with NIVO SC/IV. Conclusions: The co-primary PK and key powered secondary ORR endpoints were met, supporting the use of NIVO SC as a new option to improve healthcare efficiency. The safety profile for NIVO SC was consistent with NIVO IV. Clinical trial information: NCT04810078 .[Table: see text]

Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24mg poziotinib on an intermittent dosing schedule (cohort 1) or 16mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

Pivotal single-arm, phase 2 trial of tasurgratinib for patients with fibroblast growth factor receptor (FGFR)-2 gene fusion-positive cholangiocarcinoma (CCA).

471 Background: CCA represents ~3% of all gastrointestinal malignancies globally; it is particularly prevalent in Asian countries. Additionally, FGFR2 gene fusions occur in ~13% of intrahepatic CCA cases. Tasurgratinib (E7090) is an orally available selective inhibitor of FGFR 1–3; the recommended dose is 140 mg per day per the dose-escalation part of a first-in-human phase 1 study. In this pivotal phase 2 study, this regimen was evaluated in patients (pts) with FGFR2 fusion-positive CCA. Methods: Japanese and Chinese pts with surgically unresectable advanced or metastatic CCA were treated with tasurgratinib 140 mg PO daily. FGFR2 gene fusion was confirmed by fluorescence in situ hybridization performed in central laboratories; ≥ 1 prior chemotherapy regimen including a gemcitabine-based combination was required; pts treated with FGFR2 inhibitors were excluded. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response [PR]). Secondary endpoints included duration of response (DOR), time to response (TTR), disease control rate (DCR; CR + PR + stable disease [SD]), clinical benefit rate (CBR; CR + PR + SD lasting ≥ 23 weeks), progression-free survival (PFS), overall survival (OS), and safety. The study was considered successful if the lower limit of the ORR 90% CI was > 15% in a planned population. Tumor responses were measured every 8 weeks by RECIST v1.1 per independent imaging review. Adverse event (AE) severity was measured per CTCAE v4.03. Results: 63 Pts (Japanese: n = 28; Chinese: n = 35) were treated (median age: 55 years); 23 pts (37%) had received 1 prior regimen, all others had received ≥ 2. By the data cutoff date (March 15, 2023), 55 pts discontinued treatment (disease progression, n = 48; adverse events, n = 4; pt choice, n = 2; loss of clinical benefit, n = 1). 19 Pts (30%) had a PR; 31 pts (49%) had SD and 13 (21%) had SD for ≥ 23 weeks. The ORR was 30% (2-sided 90% CI 20.7–41.0; 95% CI 19.2–43.0); the DCR was 79% (95% CI 67.3–88.5); the CBR was 51% (95% CI 37.9–63.6). The median [m]TTR / DOR for responders were 1.87 mos (IQR 1.77–2.10; range 1.6–14.7) / 5.6 mos (95% CI 3.7–9.3; range 1.0+–14.8+). The mPFS / OS were 5.4 mos (95% CI 3.7–5.6) / 13.1 mos (95% CI 10.8–17.4). 61 Pts (97%) had ≥ 1 treatment-related AE (TRAE), most commonly hyperphosphatemia (n = 51; 81%); 18 pts (29%) had ≥ 1 grade ≥ 3 TRAE, most commonly lipase increased (n = 4; 6%). 34 Pts (54%) had a dose reduction and 18 (29%) had treatment interruption due to TRAEs. 4 Pts (6%) had a fatal AE, none related to treatment. Conclusions: Tasurgratinib had promising antitumor activity in pts with CCA harboring FGFR2 gene fusion and who received ≥ 1 prior chemotherapy regimen. The primary endpoint (ORR) met the study’s predefined success criteria. Tasurgratinib had a manageable safety profile consistent with previous reports and with the known pharmacological profile of FGFR inhibitors. Clinical trial information: NCT04238715 .

First-in-human phase 1/2 trial evaluating TAC01-CLDN18.2 autologous T cells in CLDN18.2-positive solid tumors.

TPS419 Background: CLDN18.2 is a tight junction protein expressed in differentiated gastric epithelial cells and is abnormally expressed in various solid tumor types, serving as a promising target for therapy. To date, there are no approved therapies directed against this target, but compelling data exist using monoclonal antibodies and conventional CAR T therapy. The T Cell Antigen Coupler (TAC) technology is an approach to modifying T cells ex vivo, which allows recognition and cytotoxicity of tumor cells by co-opting the natural T cell receptor. The TAC technology has a safer profile than conventional CAR T therapies and is used to create an autologous TAC01-CLDN18.2 T cell product targeting CLDN18.2. Methods: This first in-human trial (NCT05862324) is designed to assess both the safety profile and preliminary antitumor activity of TAC01-CLDN18.2 in patients with CLDN18.2+/HER2- solid tumors after ≥ 2 lines of therapy. The phase 1 dose escalation segment employs a traditional 3+3 dose-escalation design to evaluate increasing doses of TAC01-CLDN18.2 with estimated enrollment numbers of 9 to 24 subjects. The subsequent phase 2 will further evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose. With 3 cohorts, Group A will enroll up to 57 subjects with gastric and esophageal adenocarcinoma, Group B aims to enroll 10 subjects with pancreatic ductal adenocarcinoma (PDAC) while Group C will examine up to 22 subjects with ovarian and non-small cell lung cancer (NSCLC). Groups A and C will leverage a Simon 2-stage design to assess whether the treatment achieves efficacy, while Group B will be exploratory with an opportunity for cohort enrichment based on clinical data. Prior to TAC01-CLDN18.2 infusion, subjects will undergo leukapheresis and may receive bridging anticancer therapy as appropriate during cell manufacturing. CLDN18.2 expression levels will be determined centrally using a clinical trial assay validated across relevant indications. Subjects will then undergo low intensity lymphodepletion chemotherapy. A second dose of TAC01-CLDN18.2 may be administered based on prespecified safety and clinical criteria. Evaluation of DLTs will take place within a 28-day window following the first infusion. In both phases, CLDN18.2+/HER2- solid tumor patients must have completed at least two prior therapy lines except for PDAC patients who may qualify after one prior antineoplastic regimen. For phase 2, up to four prior treatment lines is permissible and definitions of eligible CLDN18.2 expression levels will be based on retrospective analysis of data from Phase 1 in association with clinical efficacy. The trial is currently in the open-enrollment stage, awaiting the inclusion of the inaugural patient. No data analysis is available as of the submission deadline. Clinical trial information: NCT05862324 .

Relationship between fluoropyrimidine (FPD) exposure and outcomes in patients with metastatic colorectal cancer (mCRC) receiving trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in the phase 3 SUNLIGHT trial.

114 Background: Standard first- and second-line chemotherapy regimens for mCRC are FPD-based. In the phase 3 SUNLIGHT trial, the addition of BEV to FTD/TPI significantly improved overall survival (OS) compared with FTD/TPI alone in patients with mCRC who had received no more than two prior chemotherapy regimens. Here, we assessed the effect of timing of prior exposure to FPD on efficacy outcomes among patients treated in SUNLIGHT. Methods: In this post-hoc analysis, OS, progression-free survival (PFS), and disease control rate (DCR) were assessed in patients treated with FPD within 2 months of enrollment (<2 months FPD-free exposure) and patients who had not received FPD for ≥2 months prior to enrollment (≥2 months FPD-free exposure). Differences in OS between FTD/TPI + BEV and FTD/TPI alone were assessed in each subgroup. The Kaplan-Meier method and log-rank test were used to compare differences in OS/PFS; DCR was compared using Fisher's exact tests. The hazard ratio (HR) for OS was estimated using a Cox proportional hazards model. Results: Of 246 patients randomized to FTD/TPI + BEV, 79 had ≥2 months FPD-free exposure and 167 had <2 months FPD-free exposure. Median OS (95% CI) was 11.8 months (9.4–not estimable) for patients with ≥2 months FPD-free exposure and 10.5 months (8.6–11.3) for patients with <2 months FPD-free exposure ( P=0.095); median PFS was 6.7 months (4.6–7.5) and 5.2 months (4.2–5.7), respectively ( P=0.043). The DCR among patients treated with FTD/TPI + BEV was 79.8% for patients with ≥2 months FPD-free exposure and 64.7% for patients with <2 months FPD-free exposure, with a between-group difference of 15.1% (95% CI: 3.6%–26.5%; P=0.018). Of 246 patients randomized to FTD/TPI alone, 91 had ≥2 months FPD-free exposure and 155 had <2 months FPD-free exposure. Median OS was 9.3 months (6.7–10.9) and 6.8 months (6.0–7.8) for patients with ≥2 and <2 months FPD-free exposure, respectively ( P=0.106) and median PFS was 3.6 months (2.1–3.9) and 2.1 months (2.0–2.7) ( P=0.002). The between-group difference in the DCR was 13.8% (50.6% vs. 36.7% for ≥2 and <2 months FPD-free exposure; 95% CI: 1.0%–26.6%; P=0.044). Compared with FTD/TPI alone, FTD/TPI + BEV resulted in longer OS in both the ≥2-month (HR 0.61, 95% CI: 0.41–0.93) and <2-month (HR 0.59, 95% CI: 0.45–0.78) groups, respectively. Conclusions: Owing to imbalances between the ≥2- and <2-month FPD-free exposure groups, the data need to be interpreted with caution. However, with both FTD/TPI + BEV and FTD/TPI alone, OS, PFS, and DCR were numerically higher in patients with ≥2 months FPD-free exposure than in those with <2 months FU-free exposure, potentially reflecting the better prognosis of the former group. The survival benefits of adding BEV to FTD/TPI were maintained regardless of the timing of exposure to FPD prior to enrollment. Clinical trial information: NCT04737187 .

Efficacy and safety of trifluridine/tipiracil in combination with bevacizumab in older and younger patients with refractory metastatic colorectal cancer: A subgroup analysis of the phase 3 SUNLIGHT trial.

111 Background: SUNLIGHT, an international, open-label, randomized, phase 3 study comparing trifluridine/tipiracil (FTD/TPI) + bevacizumab (FTD/TPI + bev) to FTD/TPI monotherapy in patients with refractory metastatic colorectal cancer (mCRC), demonstrated a 3.3-month increase in overall survival from 7.5 months with FTD/TPI monotherapy to 10.8 months with FTD/TPI + bev (HR, 0.61; 95% CI: 0.49–0.77; P<0.001). This subgroup analysis of SUNLIGHT examined efficacy and safety outcomes by age. Methods: In SUNLIGHT, patients with mCRC with ECOG PS of 0-1 and two prior treatment regimens were randomized to receive FTD/TPI + bev or FTD/TPI. A subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged <65, 65-74, and ≥75 years. Results: Among 492 randomized patients (n=246 FTD/TPI + bev; n=246 FTD/TPI), 56%, 32%, and 12% were aged <65, 65-74, and ≥75 years, respectively. Concerning overall survival, hazard ratios for FTD/TPI + bev vs FTD/TPI monotherapy were 0.65 (95% CI: 0.48–0.87), 0.64 (95% CI: 0.43–0.94), and 0.49 (95% CI: 0.27–0.90) in patients aged <65, 65-74, and ≥75 years, respectively. Regardless of age, patients receiving FTD/TPI + bev experienced improved progression-free survival and improved time to worsening of ECOG PS to ≥2. Among FTD/TPI + bev treated patients, frequency of any-cause severe adverse events (AEs) was slightly higher in the 65-74 subgroup [69% (<65); 80% (65-74); 67% (≥75 years)]. Frequency of grade 3 and 4 neutropenia was also slightly higher in the 65-74 subgroup [38% (<65); 54% (65-74); 42% (≥75 years)]. AE-related discontinuation rates were similar across age subgroups [11.6% (<65 years), 13.2% (65-74), and 16.7% (≥75 years)]. Conclusions: The results of this subgroup analysis demonstrate the efficacy benefit and tolerability of FTD/TPI + bevacizumab treatment regardless of age in refractory mCRC patients. Clinical trial information: NCT04737187 .

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (CTX-SPL9111) in advanced esophagogastric cancers in a phase 1/2 trial.

374 Background: There is a significant unmet need in esophagogastric cancers (EGC) due to limited effective treatments (Tx) and poor prognosis. Dendrimers are highly branched nanoparticles that enable sustained delivery of cytotoxic drugs and achieve selective tumor targeting via an enhanced permeability and retention effect. DEP cabazitaxel is a highly optimised dendrimer formulation of cabazitaxel. Unlike standard cabazitaxel, DEP cabazitaxel is highly water soluble, does not contain toxic excipients such as polysorbate-80 associated with anaphylaxis, and avoids the need for steroid/antihistamine pre-medication. The objective of this Phase 1/2 trial was to assess preliminary efficacy and safety of DEP cabazitaxel in patients (pts) with advanced solid tumors including EGC, for which standard cabazitaxel is not approved. Methods: In the P2 part of the trial, advanced EGC pts with measurable disease were treated with DEP cabazitaxel 20 mg/m2 cabazitaxel, the recommended Phase 2 dose, IV 3-weekly. Anti-tumour activity was assessed by RECIST v1.1, safety by CTCAE v4.03. (EudraCT 2017-003424-76). Results: Fifteen pts with advanced EGC were enrolled; 9 adenocarcinoma (ADENOCA) (3 gastric, 2 esophageal and 4 EG junction) and 6 esophageal squamous cell carcinoma (ESCC); median age 62 yrs (26–73 yrs), with all pts having ≤3 prior anticancer Tx, and the majority (9) having progressed on or immediately after 1st line Tx (1L). All had ≥1 prior platinum-based regimen and 4 pts had received prior taxanes. Pts received a median of 4.5 DEP cabazitaxel cycles without the need for routine steroid/antihistamine or primary G-CSF prophylaxis. In all evaluable pts, disease control rate (DCR) was 80%. Disease control was observed in both histological subtypes and was durable, including stable disease (SD) for up to 27 weeks and partial responses (PR) for up to 17 weeks, with objective response rate (ORR) of 30%. In EG ADENOCA pts, DCR was 100%, ORR was 33%, and median progression free survival (mPFS) was 4.0 months. In ESCC pts, DCR was 50% and ORR was 25%, with mPFS of 1.9 months. DEP cabazitaxel was well-tolerated with mostly mild (62.9%, Grade (G) 1)/moderate (20.2%, G2) treatment-related adverse events (TRAEs), including nausea, vomiting, fatigue, neuropathy, neutropenia (only 1 pt had G-CSF Tx, 1 pt had secondary G-CSF prophylaxis) and anemia, that were like those observed with standard cabazitaxel Tx. Of severe TRAEs (G3/4; 16.9%) most (80%) were observed in 2 pts, including neutropenia, anemia, thrombocytopenia, fistula, elevated liver enzymes. Conclusions: DEP cabazitaxel exhibited highly encouraging anti-tumor activity in >1L, advanced EGC in multiple anatomic locations and of different histological sub-types. The preliminary efficacy and safety results compare favorably to available treatment options and highlight the promising clinical potential of DEP cabazitaxel in advanced EGC. Clinical trial information: EudraCT 2017-003424-76 .

HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer (mCRC) refractory to anti-EGFR antibodies.

113 Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .

A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .

Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial

ObjectivesCanakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. Materials and methodsCANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. ResultsA total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2–12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5–13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76–1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3–4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm. ConclusionAdding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy.Clinical registration: NCT03626545.

Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial

ObjectiveHER2 mutations are associated with poor prognosis and are detected in 3–6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. MethodsEligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. ResultsTwenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1–4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2–40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4–67.8). Median DoR was 7.6 months (95% CI 5.6–12.3). Median PFS was 5.1 months (95% CI 1.7–7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). ConclusionsNeratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted.Trial registration number.NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).