Ayala Hubert

BACKGROUND: The risks for cancers other than breast (BC) or ovarian (OC) cancer in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers were elevated in studies of carrier families. However, case-control studies did not confirm this observation. OBJECTIVE: To compare the risks for other cancers in BRCA1/2 mutation carriers and non-carriers, all affected with BC and/or OC. Both groups share risk modifiers of BC/OC, which enabled assessment of the role of BRCA1/2 mutations. METHODS: 1098 Ashkenazi Jewish women affected with BC and/or OC were ascertained during 1995-2003; molecular testing revealed 229 BRCA1 and 100 BRCA2 carriers and 769 non-carriers. COX proportional hazard models were used to evaluate the risk of other cancers. Analyses were conducted including all other cancers or only those diagnosed after BC/OC diagnosis. RESULTS: The HRs for any other cancer were 2.6 (95% CI 1.7 to 4.2, p<0.001) and 1.8 (95% CI 0.95 to 3.6, p = 0.07) in BRCA1 and BRCA2 carriers, respectively. The corresponding colon cancer HRs were 3.9 (95% CI 1.3 to 12.1, p = 0.02) and 2.3 (95% CI 0.5 to 11.3, p = 0.3) in BRCA1 and BRCA2 carriers. The HR for lymphoma was 11.9 (95% CI 3.1 to 46.2, p = 0.001) in BRCA2 carriers. Risk estimates for other cancers after the onset of BC/OC were similar. CONCLUSION: A 2.5-fold increase in any other cancer and a fourfold risk of colon cancer were found among BRCA1 carriers. The corresponding HRs in BRCA2 carriers were non-significant, except for the markedly elevated risk of lymphoma. These results suggest a role for BRCA1/2 mutations in colorectal cancer risk in a subgroup of BC/OC-affected carriers.

PURPOSE Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. METHODS In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov ( NCT04776148 ), and has completed recruitment. RESULTS Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. CONCLUSION In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

411 Background: LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase 3 study of the safety and efficacy of lenvatinib + pembrolizumab + chemotherapy as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Methods: Eligible patients had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, patients received induction with IV pembrolizumab 400 mg Q6W (×2) + oral lenvatinib 8 mg QD + investigator choice of chemotherapy (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembrolizumab 400 mg Q6W for ≤16 doses + lenvatinib 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 may be delayed to allow for the examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all patients. Preliminary efficacy was also assessed in part 1. Objective response and disease control rate were assessed per RECIST version 1.1 by blinded independent central review. Results: In part 1, 15 pts received ≥1 dose of lenvatinib + pembrolizumab + chemotherapy. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 patients (93%), with grade 3/4 events in 8 patients (53%). 4 patients (27%) discontinued any drug because of a treatment-related AE, and no patient discontinued all drugs because of a treatment-related AE. No patients died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. Objective response was reported in 11 of 15 patients (73%; 95% CI, 45-92) who received ≥1 dose of treatment. Disease control rate was reported in 14 of 15 patients (93%; 95% CI, 68-100) who received ≥1 dose of treatment. Conclusions: In the safety run-in of LEAP-015, lenvatinib + pembrolizumab + chemotherapy was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Preliminary antitumor activity was observed for lenvatinib + pembrolizumab + chemotherapy. Part 2 will evaluate the efficacy and safety of lenvatinib + pembrolizumab + chemotherapy versus chemotherapy in this same patient population and patient accrual is ongoing. Clinical trial information: NCT04662710 .

BACKGROUND: Glecirasib, an inhibitor of Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine substitution at codon 12 (KRAS G12C), has exhibited clinical activity in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we investigated the efficacy and safety of glecirasib in patients with pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (excluding NSCLC and CRC) that rarely harbor the KRAS G12C mutation but for which effective treatment options remain limited. METHODS: We conducted and analyzed two open-label, phase I/II trials in adult patients with KRAS G12C mutant solid tumors, in which glecirasib was administered orally. The two trials had similar eligibility criteria and endpoints but differed in the regions of patient recruitment. We performed a pooled analysis of all patients, excluding NSCLC and CRC, from both trials. The primary endpoint in the pooled population was objective response rate (ORR). Efficacy and safety were assessed in patients who received at least one dose of glecirasib. RESULTS: As of June 30, 2024, the pooled analysis included 54 patients who were treated with glecirasib: 32 PDACs, 8 biliary tract cancers (BTCs), 4 small intestinal cancers, 3 gastric cancers, 2 appendiceal cancers, and 5 other tumors. At baseline, 24 received ≥ two prior lines of systemic therapy. Of the 53 efficacy-evaluable patients, the confirmed ORR was 50.9% (95% confidence interval [CI], 36.8%-64.9%), with an ORR of 46.9% (95% CI, 29.1%-65.3%) in PDAC patients. Among other solid tumors, ORR was 71.4% (5/7) in BTC, 100% (4/4) in small intestinal cancer, and 66.7% (2/3) in gastric cancer. Median progression-free survival and median overall survival were 6.9 and 10.8 months, respectively, in the overall population, and 5.5 and 10.8 months, respectively, in patients with PDAC. Treatment-related adverse events (TRAEs) of any grade occurred in 94.4% patients, with grade ≥ 3 TRAEs in 27.8%. No fatal TRAEs or TRAEs leading to treatment discontinuation occurred. CONCLUSIONS: Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05009329 and NCT05002270.