Olaparib in Patients With Solid Tumors With ATM Alterations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with ATM mutation (mut) or deletion (del) treated with Tala are reported. Methods: Eligible pts had metastatic solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Low accruing histology-specific cohorts with ATM alterations were collapsed into 1 histology-pooled cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR) and SD, and safety. Results: 29 pts with nine different solid tumors with ATM mut (n=28) or del (n=1) were enrolled. 1 pt was not evaluable for efficacy. Table shows demographics, outcomes, and toxicity. 2 PR (lung and thyroid) and 10 SD16+ (pancreas [3], prostate [2], colon, breast, kidney, rectum, stomach, thyroid) were observed in pts with ATM mut for a DC rate of 41% (1-sided 90% CI, 29 to 100) and an OR rate of 7% (95% CI, 1 to 23). The null DC rate was rejected (p=0.0005). The pt with PR and lung cancer is still on tx and has exceeded 73 wks on study as of October 2024. 8 pts had ≥1 grade 3-4 tx-related adverse event (AE). No tx-related serious AE were reported. Conclusions: Tala met prespecified criteria to declare a signal of activity in pts with solid tumors with ATM mut. Citation Format: Elie G. Dib, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Dustin Bivins, Mark Gitau, Apar K. Ganti, Arthur Winer, Vijay Suhag, Darryl Outlaw, Michael J. Hall, Olatunji B. Alese, Reza Nazemzadeh, Evan Pisick, Fengting Yan, Navid Hafez, Carmen J. Calfa, Lex Leonhardt, David DeRemer, Abigail Gregory, Dominique C. Hinshaw, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Talazoparib (Tala) in patients (pts) with solid tumors with ATM alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT228.

3115 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 28 pts with 16 solid tumors (6/28 pts had lung cancer) with BRCA1 (n=9) , BRCA2 (n=16) , or BRCA1/2 (n=3) mut were enrolled from Dec 2019 to Sept 2021. All pts were included in efficacy analyses. Demographics and outcomes are shown. 1 CR, 9 PR and 6 SD16+ were observed for a DC rate of 57% (1-sided 90% CI: 43% to 100%) and an OR rate of 36% (95% CI: 19% to 56%); the null hypothesis of a 15% DC rate was rejected (p<0.001). 11/16 pts with OR or SD16+ had a BRCA2 mut, 4 had BRCA1 mut, and 1 had both. The pt with a CR (duration of 93 wks) had non-melanoma skin cancer, with BRCA2 and ATM muts, and was microsatellite instability high with 41 muts per megabase. Pts with PR had various solid tumors; 6/9 pts had BRCA2 mut, 2 had BRCA1 mut , 1 had both. Of pts with DC, 11 had tumor types for which PARP inhibitors are not yet FDA approved. Median duration of PR was 20 wks (range, 11-80). 10/16 pts with DC had a co-alteration in the 24 homologous recombination-related genes examined, mainly ATM (3) or ARID1A (2). 13 pts had ≥1 grade 3 tx-related adverse or serious adverse events including: anemia, AST or bilirubin increase, hyponatremia, nausea, vomiting, neutrophil, platelet, or white blood cell decrease. Conclusions: Tala demonstrated antitumor activity in heavily pretreated pts with advanced solid tumors with BRCA1/2 mut. Additional study is warranted to confirm the efficacy of Tala in non-breast, non-ovarian cancer pts with BRCA1/2 mut. Clinical trial information: NCT02693535 . [Table: see text]

Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial.

BackgroundObservational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks.MethodsOur primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse‐variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided.ResultsThe genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups.ConclusionsGenetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Background CT-derived measures of body composition have been shown to have prognostic value in patients with cancer. However, few studies have compared these observations across tumor types and stages of disease. The aim of the present study was to compare body composition measures between two types of cancers, i.e. colorectal cancer (CRC), which is less inflammatory and patients maintain body composition over a longitudinal study period, whereas lung cancer (LC) is proinflammatory and patients lose more fat and muscle mass using a standard methodology. Methods Clinicopathological characteristics, including those pertaining to nutritional risk/status and systemic inflammation in patients with colorectal cancer (CRC, n = 1047) and lung cancer (LC, n = 662), were compared. The CT image at L3 was used to assess body composition. Comparison of these cohorts was carried out using the chi-square test. Binary logistic regression analysis was performed to assess the impact of clinico-pathological variables on body composition, and scatter plots were used to examine the relationship between body mass index (BMI) and CT-derived measures of body composition. Results According to CT-derived body composition, high subcutaneous (SFI) and visceral fat index (VFI) were common (>70%) in both CRC and LC. Also, low skeletal muscle index (SMI) and density (SMD) were approximately 40–50% and 60–70% in both CRC and LC. Compared with CRC, patients with LC had a higher American Society of Anaesthesia (ASA) (P < 0.001), Malnutrition Universal Screening Tool (MUST) (P < 0.001), modified frailty index (mFI) (P < 0.001), modified Glasgow Prognostic Score (mGPS) (P < 0.001), and neutrophil lymphocyte ratio (NLR) (P < 0.001) scores. On binary logistic regression analysis, MUST, mFI, and NLR were predictors of subcutaneous adiposity (P < 0.05); type of cancer, MUST, and mFI were predictors of visceral obesity (P < 0.001); age, type of cancer, MUST, and mGPS were predictors of low SMI (P < 0.001); and age, type of cancer, mFI, and mGPS were predictors of low SMD (P < 0.05). There was a similar relationship between BMI and other measures of CT-derived body composition across two types of cancers. Conclusion Obesity and low skeletal muscle mass were common in both CRC and LC cohorts despite large differences in comorbidity, nutritional risk, systemic inflammation, and survival, even when normalized for TNM stage. These observations would support the hypothesis that, although prognostic, CT derived body composition analysis primarily reflects patient constitution rather than the effect of tumor stage in patients with cancer. The systemic inflammatory response, as evidenced by mGPS, can be considered as an important therapeutic target and loss of muscle mass in patients with advanced cancer is related to the systemic inflammatory response.

Predictive factors of cetuximab efficacy for metastatic colorectal cancer (mCRC) have not been sufficiently revealed. The present study aimed to explore new predictors. A total of 30 patients with KRAS exon 2 wild-type unresectable mCRC, who had been treated with cetuximab-based regimen as first-line therapy, were retrospectively analyzed. We assessed whether gender, age, primary tumor site, RAS genotype, the Eastern Cooperative Oncology Group Performance Status (ECOG PS), metastatic status, histological grade, carcinoembryonic antigen (CEA), treatment regimen, and oxaliplatin-based adjuvant chemotherapy at baseline were associated with cetuximab efficacy. Progression-free survival (PFS) and objective response rate (ORR) were evaluated and statistically analyzed. Analysis of PFS revealed that left-sided tumor and good PS had relevance to good results. PFS among patients with left-sided CRC was longer than that among those with right-sided CRC (median, 10.6 and 3.5 months, respectively). Patients with a PS of 0 - 1 experienced significantly longer PFS than those with a PS of 2 - 3 (median, 8.6 versus 1.3 months, respectively). In analysis of ORR, high histological grade and serum CEA level showed interaction with good effect. Patients with histological grade I/II cancer experienced better ORR than those with histological grade III/IV cancer (76% versus 20%, respectively). ORR among patients with serum CEA level higher than 5.0 ng/ml was significantly higher than that among those with lower serum levels (88% versus 38%, respectively). ECOG PS, tumor location, histological grade, and serum CEA level at baseline might be useful predictors of cetuximab efficacy in the first-line treatment of mCRC.

Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial

The American Society of Clinical Oncology (ASCO) recently announced its first-ever clinical trial aimed at providing patients with advanced cancer access to molecularly targeted cancer drugs. The study also will collect “real-world” data regarding clinical outcomes to learn about applications for these drugs outside the indications approved by the US Food and Drug Administration. Known as the Targeted Agent and Profiling Utilization Registry (TAPUR), the prospective, nonrandomized trial will involve major pharmaceutical companies that will contribute drugs free of charge. TAPUR will gather information regarding the antitumor activity and toxicity of commercially available targeted drugs for a range of cancer types, including any advanced solid tumor, multiple myeloma, or non-Hodgkin lymphoma with a genomic variation known to be a drug target—a broader patient population than is normally included in clinical trials. Oncologists often use therapies approved for a specific cancer indication to treat individuals with other types of advanced cancer, but they rarely learn from that experience to benefit other patients, says Peter Paul Yu, MD, a past president of ASCO. TAPUR aims to do just that by documenting the realworld experience of patients who receive these targeted drugs. ASCO will organize operations for the study, including coordinating all collaborators. Among them will be oversight committees, pharmaceutical companies, technology firms, and community-based study sites. The participants represent an innovative, inclusive approach to studying targeted cancer drugs, according to ASCO. TAPUR not only will reach the many patients with cancer who receive their care through community-based treatment centers, but it also will provide education and support to community oncologists to help them interpret complex genomic tests. As the study proceeds, an Institutional Review Board will review the study protocol and consent form. In addition, ASCO has established 3 oversight committees, each of which will include patient representatives, clinical oncologists, statisticians, and genomic specialists. Physicians will select a drug from available TAPUR study drugs that target the identified genomic variation in the patient's tumor. If a relevant drug target match is unavailable, a physician may consult the molecular tumor board and request a review of the clinical and genomic features of the patient's case. Patients will be monitored for side effects and outcomes, including tumor response, progression-free and overall survival, and duration of treatment. At least 13 drugs that target more than 15 unique genomic variants will be provided by pharmaceutical companies. The trial will be launched at the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System, all of which run trials for the NCI and industry. Leaders hope to expand the study nationally.

1 Background: TIS is an anti-programmed cell death protein-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Primary results from this single-arm, multicenter, open-label, Phase 2 study evaluating TIS in pts with MSI-H/dMMR solid tumors, showed a clinically meaningful improvement in the objective response rate (ORR) for this patient population. Here we report results from the updated analysis (NCT03736889). Methods: Eligible adult pts with previously treated, locally advanced, unresectable/metastatic histologically confirmed MSI-H/dMMR solid tumors with ≥1 measurable lesion (RECIST v1.1) and an Eastern Cooperative Oncology Group performance status of ≤1 were enrolled. Pts received TIS 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The efficacy analysis set were all pts who received any dose of TIS with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed ORR (RECIST v1.1). Secondary endpoints included duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all IRC-assessed [RECIST v1.1]), overall survival (OS), and safety. Programmed death ligand-1 (PD-L1) immunohistochemistry assay (Ventana SP263) was applied retrospectively. Results: Between Sep 2018–Jul 2021, 80 pts were enrolled (median age 53 years; range 19–81 years) and 75 were included in the efficacy analysis set. In this updated efficacy analysis set, at a median follow-up of 15.2 months, ORRIRC was 46.7% (n = 35; 95% CI 35.1, 58.6) in all tumor types (1-sided p &lt; 0.0001), including 5 complete responses (CR) and 30 partial responses (PR). ORRIRC was 39.1% (n = 18; 95% CI 25.1, 54.6) in colorectal cancer (CRC) pts (N = 46), 55.6% (n = 5; 95% CI 21.2, 86.3) in G/GEJC pts (N = 9), and 60.0% (n = 12; 95% CI 36.1, 80.9) in other pts (N = 20). Of the pts who responded (n = 35), one patient had disease progression. Median DoR was not reached, median TTRIRC was 11.9 weeks (range 8.4–98.9) and DCR was 72.0% (95% CI 60.4, 81.8). Median PFSIRC was not reached (95% CI 7.5, not estimable [NE]). Median OS (safety analysis set) was not reached (95% CI 28.7, NE). No clear association was observed between PD-L1 expression and clinical efficacy. Treatment-emergent adverse events (TEAEs) ≥Grade 3 occurred in 48.8% (n = 39) of pts. The most common ≥Grade 3 TEAE was anemia, 10.0% (n = 8). Immune-mediated TEAEs ≥Grade 3 were 8.8% (n = 7). Conclusions: With a longer follow up time, TIS demonstrated clinically meaningful improvement in ORR in pts with MSI-H or dMMR solid tumors. TIS was generally well tolerated, with no new safety signals. These data support TIS as a new treatment option for this patient population. Clinical trial information: NCT03736889.

O-3 Efficacy and safety of entrectinib in NTRK fusion-positive gastrointestinal cancers: Updated integrated analysis of three clinical trials (STARTRK-2, STARTRK-1 and ALKA-372-001)

Elderly patients constitute a subpopulation with special characteristics that differ from those of the nonelderly and have been underrepresented in clinical trials. This study was performed to determine the efficacy and safety of irinotecan (CPT-11) in combination with fluorouracil (FU) administered as a 48-hour continuous infusion twice a month in elderly patients. Patients > or = 72 years old with metastatic colorectal cancer, Eastern Cooperative Oncology Group performance status of 0 to 1, no geriatric syndromes, and no prior treatment were treated every 2 weeks with CPT-11 180 mg/m2 plus FU 3,000 mg/m2 in a 48-hour continuous infusion. By intent-to-treat analysis, in 85 assessable patients, the objective response rate was 35% (95% CI, 25% to 46%), and stable disease was 33% (95% CI, 23% to 44%). Median time to progression was 8.0 months (95% CI, 6.0 to 10.0 months), and median overall survival time was 15.3 months (95% CI, 13.8 to 16.9 months). Toxicity was moderate. Grade 3 and 4 neutropenia, diarrhea, and asthenia were observed in 21%, 17%, and 13% of patients, respectively. Only one case of neutropenic fever occurred. There were two toxic deaths, one was a result of grade 4 diarrhea and acute kidney failure, and the other was a result of massive intestinal hemorrhage in the first cycle. The study of prognostic factors did not reveal any predictive factor of response. Response to treatment and baseline lactate dehydrogenase were the main factors conditioning progression-free and overall survival. Twice a month continuous-infusion CPT-11 combined with FU is a valid therapeutic alternative for elderly patients in good general condition.

Bortezomib for Patients with Advanced-Stage Bronchioloalveolar Carcinoma: A California Cancer Consortium Phase II Study (NCI 7003)

A proper estimation of the magnitude of the overall survival (OS) benefit from infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab versus doublets + bevacizumab is lacking because all trials that have investigated this regimen had primary end points other than OS. To test OS with higher power and to explore the interaction of treatment effect with main patient and disease characteristics, we performed an individual patient data (IPD) meta-analysis. IPD from 5 eligible trials were collected: CHARTA (ClinicalTrials.gov identifier: NCT01321957), OLIVIA (ClinicalTrials.gov identifier: NCT00778102), STEAM (ClinicalTrials.gov identifier: NCT01765582), TRIBE (ClinicalTrials.gov identifier: NCT00719797), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116). The primary end point was OS. Secondary end points were progression-free survival (PFS), objective response rate (ORR), R0 resection rate, grade 3/4 adverse events, and subgroup analyses according to clinical and molecular characteristics. A total of 1,697 patients were randomly assigned to FOLFOXIRI + bevacizumab (n = 846) or doublets + bevacizumab (n = 851). Most (78%) had an Eastern Cooperative Oncology Group performance status of 0, and the median age was 61 years. After a median follow-up of 39.9 months, patients assigned to FOLFOXIRI + bevacizumab had significantly longer OS than those assigned to doublets + bevacizumab (median, 28.9 v 24.5 months; hazard ratio [HR], 0.81; 95% CI, 0.72 to 0.91; P < .001), with no significant heterogeneity among trials (P = .39; I2 = 2%). No significant interaction effect between treatment arm and investigated characteristics was demonstrated. Patients assigned to FOLFOXIRI + bevacizumab had longer PFS (median, 12.2 v 9.9 months; HR, 0.74; 95% CI, 0.67 to 0.82; P < .001), higher ORR (64.5% v 53.6%; P < .001), higher R0 resection rate (16.4% v 11.8%; P = .007), and higher rates of grade 3/4 neutropenia (45.8% v 21.5%; P < .001), febrile neutropenia (6.3% v 3.7%; P = .019), and diarrhea (17.8% v 8.4%; P < .001). FOLFOXIRI + bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets + bevacizumab and provides advantage in PFS, ORR, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with BRAF-mutant tumors.

Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.

is important to generate evidence because this can help with reimbursement decisions. Insurers do not often pay for targeted therapies that are administered off label, because there is little evidence to suggest that the use of a particular drug leads to improved outcome. TAPUR will address that gap by shedding light on what works and what doesn’t. “If a certain drug for certain targeted therapy is not helpful, we would want to discourage physicians from writing off-label prescriptions,” Schilsky says. TAPUR, which hopes to begin enrollment at 30 sites across the US this month, is designed to run as a three-year trial. At present, five pharmaceutical companies, including AstraZeneca and Pfizer, have signed up to provide 13 targeted drugs free of charge to trial participants. The hope, Schilsky says, is to enroll roughly 800 people. The study will record changes in tumor growth as part of its evidence-generating process, and use response rate in patients to determine the primary endpoint. All trial participants will be treated with the targeted drug for 16 weeks initially, at which point researchers will assess their Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO), have begun to launch large-scale projects to gather data that could enable clinicians and researchers to discern how well targeted therapies work for cancer. One group even hopes to serve as a long-term data-collection operation that could someday unite the other organizations working to generate evidence. A major problem now is that the medical community as a whole, facing an increase in cancer-genome sequencing and the administration of targeted therapies, has no way of knowing how a given patient tolerated a prescribed treatment, explains Richard Schilsky, ASCO’s chief medical officer. To this end, the ASCO announced plans for Targeted Agent and Profiling Utilization Registry (TAPUR) at its annual conference in Chicago last June. “The advantage of doing larger-scale studies is to begin to collect information about groups of patients,” Schilsky says. “A published case report is truly an ‘n of 1’ case. There’s variability among case reports when it comes to the amount of data included [and] how representative the case is of the