This is a summary of a research article reporting the findings of the HER2CLIMB-05 trial (NCT05132582), a randomized, double-blind, placebo-controlled, international, phase III trial. The HER2CLIMB-05 trial was conducted to compare the efficacy and safety of adding tucatinib versus placebo to first-line maintenance therapy (trastuzumab and pertuzumab) following induction chemotherapy, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. The key finding of the HER2CLIMB-05 trial was that progression-free survival was significantly improved in the tucatinib arm over the control arm (24.9 vs 16.3 months). The safety profile of tucatinib plus maintenance therapy was consistent with the known toxicities of each individual drug. The HER2CLIMB-05 regimen, with its high efficacy and manageable toxicity, represents a valuable option for first-line maintenance therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.
PURPOSE:Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC. PATIENTS AND METHODS:The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival. RESULTS:IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received at least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease at baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab (P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia). CONCLUSION:The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.
BACKGROUND:The Suppression of Ovarian Function Trial (SOFT) found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. A combined analysis of SOFT and TEXT showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes. PATIENTS AND METHODS:Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, before SOFT entry with subsequent premenopausal oestradiol or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), and overall survival (OS). Additionally, 15-year Kaplan-Meier estimates, hazard ratios (HRs), and 95% confidence intervals (CIs) are reported. RESULTS:In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI of 78.6% for E+OFS, 75.7% for T+OFS, and 72.1% for T (T+OFS versus T: HR 0.82, 95% CI, 0.69-0.98, P = 0.03). In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and OS remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumors (n = 1257), the 15-year OS rate in SOFT was 81.0% with E+OFS, 77.1% with T+OFS and 76.8% with tamoxifen alone. In women under age 35 years with HER2-negative tumors (n = 241), the 15-year OS rate was 82.5% with E+OFS, 77.9% with T+OFS, and 68.1% with tamoxifen. In combined SOFT and TEXT analysis, among those with HER2-negative tumors (n = 4035), E+OFS versus T+OFS reduced distant recurrence (HR 0.75, 95% CI 0.63-0.90), with a smaller reduction in deaths (HR 0.89, 95% CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumors. CONCLUSION:Meaningful OS benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumors.
Triple Negative Breast Cancer (TNBC) poses significant challenges due to its aggressiveness, high relapse rate and mortality. Neoadjuvant immuno-chemotherapy (NAIC) is now a common treatment for early-stage TNBC before surgery. NAIC aims to eliminate viable cancer in the tumor, lymph nodes and possible occult distant metastases, shrink tumors to improve surgical outcomes and prevent disease recurrence. The Keynote-522 study revealed a 84.5% 3-year event-free survival in patients with early-stage TNBC using NAIC and improved pathological complete response (pCR) rates from 51.2% with neoadjuvant Chemotherapy to 64.8% with NAIC. A new potential method to improve clinical outcome and induce immune activation pre-surgery is through a novel local therapy in combination with NAIC that could cause increased apoptotic cell death and create personalized tumor antigens. Arnaout et al. conducted a randomized, phase 2 neoadjuvant window of opportunity trial using intratumoral (IT) INT230-6, a drug comprising vinblastine, cisplatin and a tumor dispersion and cell penetration enhancer molecule (SHAO), evaluating clinical and biological effects in women with early-stage operable BC (NCT04781725). Results in T2 to T4 tumors showed an average of over 30% necrosis in 74% of subjects at the time of surgery, with some patients having >95% tumor necrosis following a single dose. Adding immune-activating and apoptotic induced necrosis caused by INT230-6 dosed prior to NAIC in TNBC patients has the potential to increase pCR. This is a randomized, open-label multicenter phase 2 clinical study to determine the clinical activity, safety, and tolerability of IT INT230-6 in patients with early-stage, operable TNBC in combination with NAIC (cohort A) or NAIC alone (cohort B). The INT230-6 dose is dependent on tumor size. The primary endpoint is pCR in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0). Key inclusion criteria include newly diagnosed, previously untreated, locally advanced non-metastatic TNBC stage cT1c N1-3 M0 or cT2-4c N0-3 M0. Multifocal and multicentric primary tumors are allowed. Patients must have measurable disease in the breast with at least one lesion with a diameter ≥1.5 cm visible in ultrasound and injectable. Patients are either male or female, age ≥ 18 years, ECOG performance status <2, adequate bone marrow, hepatic and renal function. STATS: The sample size calculation for both cohorts is determined based on a single-stage phase II single-arm clinical trial design (A’Hern). Null hypothesis (H0): pCR rate ≤ 0.6, Alternative hypothesis (H1): pCR rate ≥ 0.8. Type I error: 10% (one-sided), Power: 80%. The duration for accrual, patient therapy and follow-up is 12, 8 and 36 months respectively. The sample size per cohort is 27 patients. The study is recruiting in Switzerland and France in up to 16 sites. By July 2025 15 of 54 patients could be enrolled, completion of accrual is expected in 2026. Preliminary safety data do not show unexpected or severe INT230-6 related adverse events. pCR results become available 6 months after the last patient starts the SOC and undergoes surgery. An exemplary case of a patient will be shown. U. Zürrer, A. Müller, O. Tredan, C. Micheloud, J. Musilova, R. Popescu, T. Schmid, L. Rossi, M. Schwitter, M. Vetter, M. Niemeyer, I. Witzel, A. Patsouris, S. Ladoire, J. Martin-Babau, A. Deleuze, M. Robert, L. H. Bender, M. Joerger. Intratumoral Injections of INT230-6 Prior to Neoadjuvant Immuno-chemotherapy in Early-Stage Triple Negative Breast Cancer: Early observations from INVINCIBLE-4-SAKK 66/22 (NCT06358573), a Phase II Randomized Controlled Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-16.
Cancer survivors face an increased risk of second primaries, but adherence to cancer screening and prevention recommendations remains limited. Post-treatment follow-up visits represent teachable moments for health promotion, including prevention of second primary cancers. We assessed practices and perceptions of second cancer screening and prevention among French hospital-based oncology health care professionals. An anonymous online survey using Likert scale was conducted. Clustering identified three prevention activity profiles (low, intermediate, high), and multinomial logistic regression explored associated factors. The median declared promotion activity of the 415 respondents was 8 for mammographic screening ([interquartile range: 5-10), 7 (2-9) for cervical cancer screening, 5 (1-7) for colorectal screening, 9 (7-10) for smoking cessation, and 7 (5-9) for alcohol control. Seventy-five percent of respondents addressed obesity management if indicated. Perceived importance and feasibility of secondary prevention activities were high [9 (7-10) and 8 (6-10)]. A high prevention activity profile was associated with greater perceived importance of secondary prevention [odds ratio (OR) per one-point Likert-scale increase = 1.1, 95% confidence interval (CI): 1.04-1.2] and its feasibility (OR = 1.1, 95% CI: 1.06-1.14); and managing head and neck cancer patients (OR = 7.64, 95% CI 1.55-37.8). Lung and sarcoma specialists were less likely to be in the high prevention activity group. Hospital-based oncology health care professionals are aware of and engaged in second primary cancer prevention, though activity levels vary. Its generalization, organization, and development could improve cancer survivors' adherence to cancer prevention recommendations, and improve health impacts.
