Adverse Events Of Grade Research Articles

Understanding the safety and toxicity profile of durvalumab for Black patients with lung cancer.

e20051 Background: Constituting 12.2% of all new cancer diagnosis in 2023,Lung cancer continues to be among the most common cancers in the US. According to statistics 1 in 16 black males and1 in 20 black females are likely to develop lung cancer in their lifetime.The results of the PACIFIC trial changed the paradigm of management in non-resectable NonSmall Cell Ca and made Durvalumab the standard of care. The toxicity profile of the drug were extensively studied in the study however, only 2% (n-14) of the study population was Black. More studies are required to understand the tolerability and toxicity profile of the drug in the Black population. Methods: This is a retrospective study. Study population consisted of 55 self-identified African Americans diagnosed with stage 3 Non-small Cell Ca who received Durvalumab for consolidation therapy after chemo radiation at a large safety net hospital between 2018-2023.Their charts were reviewed to study: 1. The development of any grade- known adverse side effects of the drug. 2. The tolerability of the drug- assessed as the lack of severe toxicities resulting in discontinuation of the drug. 3. Appearance of any peculiar adverse effects not previously known. 4. Adverse side effects warranting the use of more healthcare resources, like ED visits and hospital admissions for adverse effects. The results were then compared to the results of the PACIFIC trial. Results: 52.7% (n=29) developed known adverse effects of the drug-any grade.20 % (n=11) developed severe adverse effects leading to discontinuation of therapy.32.7%(n=18) were able to tolerate completion of therapy in-spite of adverse effects. 16.3% ( n=9) required ED visits/ hospital visit due to immunotherapy adverse effects. ADRs leading to discontinuation of therapy-pneumonitis -9%, Debilitating Chest Pain-1.8%, Hyperglycemia- 1.8%, severe fatigue-1.8%, atrial fibrillation-1.8%, Autoimmune hepatitis -1.8% and Pan uveitis -1.8%. Other adverse effects are listed in the table. Conclusions: Based on our results, AA are more likely to develop any grade adverse effects than was estimated in the PACIFIC trial, however, the percentage of the AA population discontinuing therapy due to severe adverse effect was lower. While the occurrence of most common adverse effects including Pneumonitis was comparable to the PACIFIC trial, thyroid dysfunction – both hypo and hyperthyroidism was about 3 times more in the AA population. All the thyroid dysfunctions noted were G1 and G2, and did not require discontinuation of therapy. We therefore, recommend providers to be more watchful for signs and symptoms suggestive of thyroid dysfunction when treating AA patients with Durvalumab. [Table: see text]

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

BackgroundPatients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).MethodsIn a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.ResultsA total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).ConclusionsIn this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Switch to long-acting cabotegravir and rilpivirine in virologically suppressed adults with HIV in Africa (CARES): week 48 results from a randomised, multicentre, open-label, non-inferiority trial

Long-acting injectable cabotegravir and rilpivirine is licensed for individualised treatment of HIV-1 infection in resource-rich settings. Additional evidence is required to support use in African treatment programmes where demographic factors, viral subtypes, previous treatment, and delivery and monitoring approaches differ. The aim of this study was to determine whether switching to long-acting therapy with injections every 8 weeks is non-inferior to daily oral therapy in Africa. CARES is a randomised, open-label, non-inferiority trial being conducted at eight sites in Uganda, Kenya, and South Africa. Participants with HIV viral load below 50 copies per mL on oral antiretroviral therapy and no history of virological failure were randomly assigned (1:1; web-based, permuted blocks) to receive cabotegravir (600 mg) and rilpivirine (900 mg) by intramuscular injection every 8 weeks, or to continue oral therapy. Viral load was monitored every 24 weeks. The primary outcome was week 48 viral load below 50 copies per mL, assessed with the Food and Drug Administration snapshot algorithm (non-inferiority margin 10 percentage points) in the intention-to-treat exposed population. This trial is registered with the Pan African Clinical Trials Registry (202104874490818) and is ongoing up to 96 weeks. Between Sept 1, 2021, and Aug 31, 2022, we enrolled 512 participants (295 [58%] female; 380 [74%] previous non-nucleoside reverse transcriptase inhibitor exposure). Week 48 viral load was below 50 copies per mL in 246 (96%) of 255 participants in the long-acting therapy group and 250 (97%) of 257 in the oral therapy group (difference -0·8 percentage points; 95% CI -3·7 to 2·3), demonstrating non-inferiority (confirmed in per-protocol analysis). Two participants had virological failure in the long-acting therapy group, both with drug resistance; none had virological failure in the oral therapy group. Adverse events of grade 3 or greater severity occurred in 24 (9%) participants on long-acting therapy and ten (4%) on oral therapy; one participant discontinued long-acting therapy (for injection-site reaction). Long-acting therapy had non-inferior efficacy compared with oral therapy, with a good safety profile, and can be considered for African treatment programmes. Janssen.

Efficacy and safety of anti-angiogenic drug monotherapy and combination therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials.

As the development of novel anti-angiogenic drugs and the continuous evolution of guideline recommendations, the efficacy and safety of anti-angiogenic agents in ovarian cancer (OC) remains unclear. Consequently, a meta-analysis was carried out to assess the efficacy and safety of anti-angiogenic drug monotherapy and combination therapy for OC. An exhaustive literature review was performed across multiple databases, including PubMed, Embase, Web of Science, and Cochrane, encompassing all relevant randomized controlled trials (RCTs) up until 6 April 2024. The evaluation of efficacy outcomes incorporated progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Safety was assessed through the occurrence of any grade adverse events (AEs) and grade ≥3 AEs. Synthesis of the data involved the calculation of hazard ratios (HRs), relative risks (RRs), and their corresponding 95% confidence intervals (CIs) and prediction intervals (PIs). Trial sequential analysis was executed employing TSA v0.9.5.10 Beta software, STATA 12.0, and R software 4.3.1. In this meta-analysis, 35 RCTs were included, encompassing 16,199 subjects in total. The overall analysis indicated that anti-angiogenic drug combination therapy significantly improved PFS (HR [95% CI] = 0.678 [0.606-0.759], 95% PI: 0.415-1.108), OS (HR [95% CI] = 0.917 [0.870-0.966], 95% PI: 0.851-0.984), and ORR (RR [95% CI] = 1.441 [1.287-1.614], 95% PI: 1.032-2.014), but also increased the incidence of grade ≥3 AEs (RR [95% CI] = 1.137 [1.099-1.177], 95% PI: 1.011-1.252). The analysis did not corroborate any benefit of anti-angiogenic monotherapy over placebo concerning PFS (HR [95% CI] = 0.956 [0.709-1.288], 95% PI: 0.345-2.645) and OS (HR [95% CI] = 1.039 [0.921-1.173], 95% PI: 0.824-1.331). However, it was observed that monotherapy with anti-angiogenic drugs did increase the incidence of any grade AEs (RR [95% CI] = 1.072 [1.036-1.109], 95% PI: 0.709-1.592). Our study confirmed the PFS, OS, and ORR benefits of anti-angiogenic drug combination therapy for OC patients. The efficacy results of anti-angiogenic monotherapy necessitates further evaluation as more RCTs become available. Clinicians should be vigilant of AEs when administering anti-angiogenic agents in a clinical setting.

Romiplostim for Treatment of Children and Young Adults With Severe Aplastic Anemia and Myelodysplastic Syndrome.

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5µg/kg/week, with dose escalation of 2.5µg/kg/week (maximum, 20µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2y). Median romiplostim dose was 10µg/kg/week (range: 5 to 17.5µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.

Preoperative Tyrosine Kinase Inhibitors Before Percutaneous Cryoablation for Clinical T1b Renal Tumors.

Purpose To treat renal cell carcinoma, local ablative therapy is a viable alternative treatment option. Traditionally, cryoablation has been used for the treatment of T1a renal tumors. However, recent technological developments have expanded its application to encompass select T1b renal tumors. Here, we present a retrospective study of the utilization of preoperative tyrosine kinase inhibitors(TKIs) to induce tumor shrinkage and achieve favorable outcomes in percutaneous cryoablation (PCA). Methods We retrospectively evaluated the data from nine patients with clinical T1b renal tumors who underwent PCA. Six patients with TKI pretreatment at our institution between 2016 and 2018 were included in the study. We evaluated the safety and efficacy of preoperative TKIs prior to PCA. Results All patients received axitinib with a median treatment duration of 80.5 days (IQR: 49-85). All patients experienced tumor shrinkage (median: 13.5 mm; IQR: 7-16); five experienced downstaging to T1a following tumor shrinkage. There were no severe adverse events (common terminology criteria for adverse events (CTCAE) grade ≥ 3) in TKIs. After the discontinuation of TKIs for two weeks, all PCA procedures were performed successfully without any severe complications. During a median follow-up of 46 months, no local recurrence was observed in any of these cases. Conclusion In cases with large renal tumors, TKI pretreatment prior to PCA had potential benefits in terms of tumor shrinkage and long-term local control rate. Further well-designed studies in larger populations are needed to validate our findings.

Targeted microwave ablation for prostate cancer (FOSTINE1b): a prospective 'ablate-and-resect' study.

To assess histopathological outcomes, as well as feasibility and safety of targeted microwave ablation (TMA) via the Trinity® system (KOELIS, La Tronche, France). Prospective, single-institution, interventional Phase IIa study with an 'ablate-and-resect' design. In all, 11 patients diagnosed with localised prostate cancer (PCa) underwent TMA via the Trinity system under conscious sedation in an outpatient setting using a single transrectal TATO® 18-G antenna with different treatment regimens. Magnetic resonance imaging (MRI) and robot-assisted radical prostatectomy (RARP) were conducted at 7 days and 1 month after TMA, respectively. Nine patients received RARP, and two patients chose to withdraw their consent following TMA. These men chose an active surveillance protocol upon confirmation of a low-risk prostate cancer diagnosis. Functional outcomes and adverse events were evaluated at baseline and follow-up visits using validated questionnaires. Prostate volumetry and confirmation of necrosis were carried out through MRI and whole-mount histopathological examination. The TMA was successfully executed, and all patients were discharged on the same day. No severe adverse events (Common Terminology Criteria for Adverse Events Grade ≥3) were reported at the 7-day and 1-month follow-up visits. Additionally, no declines were observed in urinary, sexual and ejaculation functional outcomes. T1-weighted MRI revealed clear and well-defined ablation zones. The RARP was executed without difficulty, particularly during the dissection of the posterior plane. As a result, no intraoperative complications were encountered. Histopathological assessment on surgical specimens confirmed the absence of viable cells, indicating complete necrosis of the ablative zone if a power intensity >10 W was used during TMA. Ablation zone volumetry revealed no notable distinctions between the three-dimensional segmentation of the virtual ablation zone at TMA (median volume: 2 mL) and MRI (median volume: 1.923 mL). Conversely, a significant reduction was noted in the surgical specimen (median volume: 0.221 mL). Targeted microwave ablation via the Trinity system for localised PCa treatment proves to be a secure and feasible procedure, with complete necrosis evidence within the ablation zone on surgical specimens.

Prognostic value of sarcopenia in the patients with locally advanced nasopharyngeal carcinoma.

Sarcopenia, characterized by loss of muscle mass index (SMI), serves as a diagnostic indicator for malnutrition and has been shown to influence cancer treatment outcomes. The objective of this study was to investigate the prognostic significance of sarcopenia on the locally advanced nasopharyngeal carcinoma (laNPC) patients. 545 patients with stage III-IVa NPC were included in this retrospective study. Sarcopenia was defined using the skeletal muscle index (SMI) determined at the C3 level based on baseline MRI. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). The results of the multivariate analysis revealed that sarcopenia group (HR = 2.82, 95% CI 1.96-4.06, P < 0.01), T4 stage (HR = 1.64, 95% CI 1.24-2.15, P < 0.01), N3 stage (HR = 1.91, 95% CI 1.52-2.40, P < 0.01), comorbidities (HR = 2.08, 95% CI 1.45-2.97, P < 0.01), and any adverse event grade 3-4 (HR = 1.48, 95% CI 1.04-2.01, P = 0.03) were identified as independent risk factors that significantly impacted the OS. Additionally, sarcopenia group (HR = 2.40, 95% CI 1.73-3.33, P < 0.01), T4 stage (HR = 1.50, 95% CI 1.17-1.92, P < 0.01), N3 stage (HR = 1.80, 95% CI 1.46-2.22, P < 0.01), sarcopenia group (HR = 2.40, 95% CI 1.73-3.33, P < 0.01), and any adverse event grade 3-4 (HR = 1.45, 95% CI 1.04-2.01, P = 0.03) were found to have a significant impact on PFS. Sarcopenia was identified as a prognostic factor for patients with laNPC. Furthermore, T stage, N stage, comorbidities, and any adverse event grade 3-4 were identified as independent prognostic factors for laNPC.

Prognostic role of circulating cytokines and inflammation indexes for avelumab maintenance in metastatic urothelial carcinoma.

Avelumab maintenance after first-line platinum-based chemotherapy represents a cornerstone for the treatment of metastatic urothelial carcinoma (mUC). However, identifying prognostic biomarkers is paramount for optimizing patients' benefits while minimizing toxicity. Cytokines represent circulating mediators of the complex interaction between cancer, the immune system, and inflammation. Inflammation, a hallmark of cancer, can be expressed by circulating factors. In different tumor subtypes, peripheral blood biomarkers, such as circulating cytokines, and systemic inflammatory indexes, have been addressed as potential prognostic factors for immune checkpoint inhibitors. However, their role in mUC still needs to be determined. Between February 2021 and April 2023, we prospectively collected plasma cytokines and inflammation indexes in 28 patients with mUC before starting avelumab as first-line maintenance. The primary endpoint was the relationship between baseline cytokines and inflammatory indexes with the clinical benefit (CB), defined as the number of Responders. Secondary endpoints included the correlation of baseline cytokines and inflammatory indexes with progression-free survival (PFS), overall survival (OS), and the number and grade of immune-related adverse events. High pre-treatment levels of interferon (IFN)-γ and interleukin (IL)-2, and low levels of IL-6, IL-8, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic-inflammation index (SII) were associated with clinical benefit and longer survival. In the multivariate analysis, low IL-8, NLR, and SII levels maintained a positive prognostic value for OS. Our data suggest that, in mUC patients receiving avelumab, pre-treatment levels of plasma cytokines and inflammatory indexes may serve as potential prognostic biomarkers for response and efficacy. In particular, patients with signs of pre-therapeutic inflammation showed a significantly lower response and survival to avelumab. On the contrary, low systemic inflammation and high levels of cytokines characterized responders and longer survivors.

Single-centre observational study of the safety and efficacy of thoracoscopy under local anaesthesia for the management of thoracic infections

ObjectivesThoracoscopy under local anaesthesia is widely performed to diagnose malignancies and infectious diseases. However, few reports have described the use of this procedure for diagnosing and treating intrathoracic infections. This study aimed to evaluate the safety and efficacy of thoracoscopy under local anaesthesia for the management of intrathoracic infections.ResultsData from patients who underwent thoracoscopy procedures performed by chest physicians under local anaesthesia at our hospital between January 2018 and December 2023 were retrospectively reviewed. We analysed their demographic factors, reasons for the examinations, diseases targeted, examination lengths, anaesthetic methods used, diagnostic and treatment success rates, as well as any adverse events. Thirty patients were included. Of these, 12 (40%) had thoracoscopies to diagnose infections, and 18 (60%) had them to treat pyothorax. In terms of diagnosing pleurisy, the causative microorganism of origin was identified via thoracoscopy in only three of 12 (25.0%) patients. For diagnosing pyothorax, the causative microorganism was identified in 7 of 18 (38.9%) patients. Methicillin-resistant Staphylococcus aureus was the most common causative microorganism identified. The treatment success rates were very high, ranging between 94.4 and 100%, whereas the identification rate of the causative microorganisms behind infections was low, ranging between 25.0 and 38.9%. The most frequent adverse events included perioperative hypoxaemia and pain. There were two (6.7%) serious adverse events of grade ≥ 3, but none resulted in death.ConclusionsThe efficacy of managing intrathoracic infections through thoracoscopy under local anaesthesia is commendable. Nonetheless, the diagnostic accuracy of the procedure, regarding the precise identification of the causative microorganisms responsible for intrathoracic infections, persists at a notably low level, presenting a substantial clinical hurdle.

Patient perspectives in adverse event reporting after vaginal apical prolapse surgery

BackgroundMany clinical trials use systematic methodology to monitor adverse events (AE) and determine grade (severity), expectedness, and relatedness to treatments as determined by clinicians. However, patient perspective in the process remains lacking. ObjectivesTo compare clinician versus patient grading of AE severity in a urogynecologic surgical trial. Secondary objectives were to estimate the association between patient grading of AEs with decision-making and quality of life outcomes and to determine if patient perspective changes over time. Study DesignThis was a planned supplementary study, “Patient-Perspectives in Adverse Event Reporting” (PPAR), to a randomized trial comparing 3 surgical approaches to vaginal apical prolapse. In the parent trial, AEs experienced by patients were collected per a standardized protocol every 6 months where clinicians graded AE severity (mild, moderate, severe/life threatening). In this sub-study, we obtained additional longitudinal patient perspectives for 19 predetermined “PPAR AEs”. Patients provided their own severity grading (mild, moderate, severe/very severe/ life threatening) at initial assessment and at 12 and 36 months postoperatively. Clinicians and patients were masked to each other’s reporting. The primary outcome was the interrater agreement (kappa statistic, κ) for AE severity between the initial clinician and patient assessment, combining patient grades of mild and moderate. Association between AE severity and the Decision-Regret Scale (DRS), Satisfaction with Decision Scale (SDS), the Short-Form Health Survey-12 (SF-12), and Patient-Global Impression of Improvement (PGI-I) scores were assessed utilizing Spearman’s correlation coefficient (ρ) for continuous scales, Mantel-Haenszel chi-squared test for PGI-I, and T-tests or chi-squared tests comparing assessments of severe vs other grades. To describe patient perspective changes over time, the intra-observer agreement was estimated for AE severity grade over time using weighted kappa-coefficients. ResultsOf 360 patients randomized, 219 (61%) experienced a total of 527 PPAR AEs (91% moderate and 9% severe/life threatening by clinician grading). Mean patient age was 67 years, 87% were White, and 12% Hispanic. Of patients reporting any PPAR event, the most common were urinary tract infection (61%), de novo urgency urinary incontinence (35%), stress urinary incontinence (22%), and fecal incontinence (13%).Overall agreement between clinician and participant grading of severity was poor (κ=0.24 (95%CI 0.14, 0.34). Of 414 AEs clinicians graded as moderate, patients graded 120 (29%) mild, and 80 (19%) severe. Of 39 AEs graded severe by clinicians, patients graded 15 (38%) mild or moderate. Initial patient grading of the most severe reported AE was mildly correlated with worse DRS (ρ=0.2, p=0.01), SF-12 (ρ=-0.24, p<0.01) and PGI-I (p<0.01). There was no association between AE severity and SDS. Patients with an initial grading of “severe” had more regret, lower quality of life, and poorer global impressions of health than those whose worst severity grade was mild (p<0.05). Agreement between the patients’ initial severity and later timepoints was fair at 12 months (κ=0.48 (95% CI 0.39, 0.58)) and 36 months (κ=0.45 (95% CI 0.37, 0.53)). ConclusionsClinician and patient perceptions of AE severity are discordant. Worse severity from the patient perspective was associated with patient-centered outcomes. Including the patient perspective provides additional information for evaluating surgical procedures.

The safety of modified, all-oral shorter tuberculosis regimens in Armenia.

The implementation of modified, all-oral shorter regimens for treatment of rifampicin-resistant tuberculosis has started in Armenia since August 2020 under the conditions of operational research. This study aims to evaluate the safety and effectiveness of shorter regimens. We evaluated cumulative incidence rates of serious adverse events, adverse events of grade 3 and greater and events resulting in treatment modifications or suspension for 52 study participants. A new, different pattern of adverse events emerged compared with the previous evaluations of drug safety of treatment for rifampicin-resistant tuberculosis. Arthralgia (23.1%) and peripheral neuropathy (21.2%) took leading positions among the adverse events resulting in modifications of treatment. Some adverse events of interest (prolonged QT interval, elevated liver enzymes and anemia) remained relevant for the patients receiving new combinations of anti-TB drugs. The other adverse events (impaired hearing, acute kidney injury and hypokalemia) lost their significance for safety surveillance of rifampicin-resistant tuberculosis treatment. One unexpected serious adverse event (lymphoproliferative skin lesion) brought to a "failed treatment" outcome. The other serious adverse event was anemia. The shorter regimens proved to be safe and effective for treatment of rifampicin-resistant tuberculosis, but proper follow-up of adverse events is necessary.

Abstract PO1-18-07: Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer

Abstract BACKGROUND: The amplification of genes PDL-1, PDL-2, and JAK2 on chromosome 9p24, known as the PDJ amplicon, has been identified in 15% of triple negative breast cancer (TNBC) and is associated with tumor infiltrating lymphocytes and elevated JAK2 mRNA, suggesting a coordinated inflammatory response in TNBC. Adding pembrolizumab to chemotherapy in KEYNOTE trials 355 and 522 has validated the use of PD-1 blockade in TNBC and redefined the standard of care. Despite preclinical data suggesting a role for targeting the IL- 6/JAK2/STAT3 pathway, the JAK1/JAK2 inhibitor ruxolitinib has not shown efficacy as a single Agent in breast cancer. This is the first phase I clinical trial evaluating the combination of pembrolizumab and ruxolitinib in the treatment of metastatic TNBC. METHODS: We conducted a phase I clinical trial with accrual from 2018 to 2023 at Mayo Clinic Arizona. Patients (n=12) received 200 mg of IV pembrolizumab per cycle (every 3 weeks) with 3+3 dose escalation of oral ruxolitinib twice a day (dose level 0: 10 mg PO BID, level 1: 15 mg PO BID, level 2: 20 mg PO BID). The primary endpoint was to determine the maximum tolerated dose (MTD) of ruxolitinib and secondary endpoints were treatment safety and efficacy. Clinical response was assessed by computed tomography of the chest, abdomen, and pelvis every 3 cycles. PD-L1 expression in tumor was measured by immunohistochemistry (IHC). The effect of the combined therapies on T and B cell populations were assessed by flow cytometry and antibody profiling of 695 tumor antigens and 8 viral antigens by nucleic acid protein programmable array. RESULTS: Twelve female patients with chemotherapy refractory metastatic TNBC were treated on study. All received 200 mg IV pembrolizumab every cycle. Due to rapid disease progression of three patients early after treatment initiation, eligibility was restricted to prohibit patients with extensive pulmonary disease or elevated LDH. Those patients were excluded from efficacy or correlative analysis. The most common toxicities were transaminitis (n=12), anemia/leukopenia (n=12), and fatigue (n=9). The majority of adverse events were grade 1 and occurred at dose level 2. There were 5 adverse events grade 3 or higher: respiratory or thoracic complications (n=3), hypertension (n=1), and abdominal pain (n=1), but MTD was not established. The median number of cycles was 4 for each dose level (range n=2.0-9.0) and the median time to progression was 3 months (range n=1.4-6.3). No patient had tumor response by RECIST v1.1 criteria and there was no association of disease stability with PD-L1 tumor expression by IHC. Circulating antibodies to tumor antigens remained stable, and viral-specific antibodies mildly decreased by month 2 in all patients at dose levels 0 and 1. Of the 7 patients reactive to TRIM21 autoantibodies, 2 patients had a transient increase at 2 months. CONCLUSIONS: The combination of pembrolizumab with ruxolitinib was well tolerated at all dose levels, and the number but not the severity of adverse events increased with higher ruxolitinib dose. Two of six patients in dose level 0 and 1 had stable disease for six months on treatment, suggesting that the lower dose levels of ruxolitinib (i.e. 10 mg PO BID) may have more activity in combination with pembrolizumab. Citation Format: Anelia Kassi, Jacqueline Carmona, Sarah M. Green, Heidi Kosiorek, Michael T. Barrett, Barbara A. Pockaj, Donald Northfelt, Karen S. Anderson. Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-07.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, &amp;gt; 9 responders were need in stage 1 (n=18) for the study to continue, and &amp;gt;19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-12.

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Abstract PO1-20-03: Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. However, there is no effective treatment or preventative measure for CIPN. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. Our group previously completed a single-arm phase IIA pilot trial of women who developed National Cancer Institution Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 2 CIPN during weekly paclitaxel for stage I-III breast cancer. The result suggested an acupuncture intervention for grade 2 CIPN might slow CIPN progression during chemotherapy. However, the role of acupuncture still needs to be better defined. Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. The study will include two phases: screening and intervention. In the screening phase, eligible patients will consent and receive CIPN screening each week. Patients who develop grade 1 CIPN or higher based on NCI-CTCAE version 5.0 will be consented to the intervention phase and randomized to receive either weekly RA or SA using a standardized, semi-fixed protocol developed in our preliminary studies to improve CIPN pain. Eligibility criteria for the screening phase: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care. Eligibility criteria for the intervention phase: in additional to the screening phase eligibility criteria, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures, including randomization to one of the two possible acupuncture treatments. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 20 participants in the intervention phase by the end of June 2023; the target accrual is 80 participants. Contact information for people with a specific interest in the trial: W. Iris Zhi, MD, PhD, zhiw@mskcc.org. ClinicalTrails.gov Identifier: NCT05458284. Citation Format: W. Iris Zhi, Lauren Taylor, Raymond Baser, Matthew Weitzman, Qing Li, Christina Seluzicki, Ting Bao, Jun Mao. Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-03.

Abstract PO2-17-12: Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC

Abstract Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-Lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies, vaccination with aLA provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and inhibited growth of established 4T1 transplantable breast tumors in BALB/c mice (PMID: 20512124). Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 are considered dose-limiting toxicities (DLTs). Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. Seven (7) of 10 patients assayed to date have met protocol specified definitions of an immune response based on ELISpot assays to determine frequencies of T cells producing IFNγ and IL-17 in response to recombinant aLA. Assays for an additional 6 patients will be available in September 2023. Conclusion: Dose level ≤ 2 appears to be the maximum tolerated dose. Based on immune response, additional intermediate dose levels may be studied. An additional cohort of patients receiving concurrent anti-PD1 treatment is being accrued. Accrual of patients with BRCA1/2 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Table 1 Worst Toxicity by Dose Level Citation Format: Justin Johnson, Emily Rhoades, Holly Levengood, Halle Moore, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Rachel Swartz, Holly Pederson, Elena Haury, Azka Ali, Tiffany Onger, Andrew Sciallis, Zahraa Al-Hilli, Wei Wei, Thaddeus Stappenbeck, George Budd. Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-12.

Abstract PO2-05-01: Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-01.

Abstract GS01-03: Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial

Abstract Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane chemotherapy (arm A) versus chemotherapy alone (arm B) in early-stage TNBC. Methods: ALEXANDRA/IMpassion030 (NCT03498716) aimed to randomize (1:1) 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients were stratified by type of surgery (breast conserving versus mastectomy), nodal status (0 versus 1-3 versus &amp;gt;=4 nodes), and centrally assessed PD-L1 status (IC 0 vs &amp;gt;=1% ). Adjuvant chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab (Arm A) or the same chemotherapy regimen (T-EC/AC) alone (Arm B). The primary endpoint was invasive disease-free survival (iDFS); secondary endpoints included, iDFS in the PD-L1 positive and lymph node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). On the 14th of November 2022, following an IDMC recommendation, the study accrual was temporarily stopped. In February 2023, the protocol was amended in order for the IDMC to perform an early interim analysis of efficacy and futility, at approximately 62% of the planned (390) iDFS events. The futility boundary was set to a Hazard Ratio (HR) &amp;gt; 1. Results: The IDMC recommendations of 15th March 2023 reported that the primary endpoint crossed the futility boundary, accrual to the study was permanently stopped and the experimental treatment was discontinued. Between August 2018 and November 2022, the study enrolled 2199 patients, with 1101 randomised to the atezolizumab arm (A) and 1098 to the control arm (B). At a median follow-up of 25.3 months, 239 (10.9%) iDFS events were observed in the 2199 enrolled patients; 127 versus 112 iDFS events were observed (61.3% of 390) in the A versus B arms respectively, HR 1.12, (95% confidence interval, CI, 0.87, 1.45). In the PD-L1 positive subgroup, (1567/2199 patients, 71.3%), 77 versus 73 iDFS events were observed in the A versus B arms respectively, HR 1.03, (95% CI 0.75, 1.42). Among patients with lymph node positive tumors (1066/2199 patients, 48.5%), 86 versus 66 iDFS events were observed in the A versus B arm respectively, HR 1.41, (95% CI 1.02, 1.96). Incidence of adverse events grade &amp;gt;=3 was 58.01% versus 48.15% in the A versus B arms, including death in 1.01% (11) and 0.55% (6) of patients, respectively. Conclusions: Crossing the pre-specified futility boundary of HR &amp;gt; 1 provides evidence that adjuvant atezolizumab is very unlikely to improve invasive disease-free survival when added to adjuvant anthracycline and taxane based chemotherapy in patients with stage II-III triple-negative breast cancer. With longer treatment exposure in the atezolizumab arm (A), adverse events were more frequent but consistent with the atezolizumab safety profile. No new or unexpected safety issue was identified. Citation Format: Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Steve Chui, Max Dieterich, Thomas Perretti, Guenther Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, José Zarbá, Marcus Schmidt, Henry Gomez, Angel Guerrero-Zotano, Luca Moscetti, Joanne Win Yang Chiu, Carter DuFrane, Vanessa Honvault, Rosa Altarcheh, Luciana Molinero, Andrew Ellingson, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Gal-Yam, Xavier Gonzalez-Farré, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Ivan Sinielnikov, Zimina Anastasia, Aleksandr Vasiliev, Esther Shearer-Kang, Eric Winer, Diogo Martins-Branco, Shona Fielding, David Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-03.

Abstract PS02-01: Efficacy, safety, and quality of life with ribociclib + endocrine therapy in elderly patients with HR+/HER2– advanced breast cancer across the MONALEESA-2, -3, and -7 trials

Abstract Background: Ribociclib (RIB) + endocrine therapy (ET) showed statistically significant progression-free survival (PFS) and overall survival (OS) benefits in MONALEESA-2, -3, and -7 in patients (pts) with HR+/HER2− advanced breast cancer (ABC). Here, we report efficacy, safety, and quality of life (QOL) with RIB + ET in elderly pts in the MONALEESA trials. Methods: Data were pooled from the MONALEESA-2, -3, and -7 trials of pre- and postmenopausal pts with HR+/HER2− ABC treated with first-line RIB + ET or placebo (PBO) + ET. The tamoxifen cohort in MONALEESA-7 and pts with early relapse were excluded from this analysis. PFS, OS, and time to first chemotherapy (TTC) were analyzed in pts &amp;lt;65 y, 65- &amp;lt;75 y, and ≥75 y using Kaplan-Meier methods. Time to definitive deterioration (TTD) by ≥10 points in global health status (GHS) was analyzed across age subgroups using Kaplan-Meier methods. Results: Of the 1229 pts included in this analysis, 773 (62.9%) were &amp;lt;65 y, 335 (27.3%) were 65- &amp;lt;75 y, and 121 (9.8%) were ≥75 y. There were minor differences in baseline characteristics between the age groups: slightly higher % of pts in the ≥75 y group with a ECOG status of 1 and slightly higher % of de novo disease in the &amp;lt;65 y group (Table). Regardless of age, a PFS and OS benefit was seen with RIB + ET vs PBO + ET (Table). RIB + ET also delayed the median TTC in all age groups. In the RIB + ET group, the most common first subsequent antineoplastic treatment was hormonal therapy alone ( &amp;lt;65 y, 26.3%; 65- &amp;lt;75 y, 41.6%; ≥75 y, 38.1%). In the ≥75 y subgroup, pts in the RIB + ET arm (6.3%) less frequently used chemotherapy alone as the first subsequent antineoplastic treatment vs the PBO + ET (24.5%) arm. In pts &amp;lt;65 y, safety results were consistent with those in the overall trial population. In pts 65- &amp;lt;75 y and ≥75 y, the most common any grade adverse events (AEs) with RIB + ET vs PBO + ET were neutropenia (67.6% vs 5.4% and 52.9% vs 3.8%), nausea (52.7% vs 32.0% and 52.9% vs 40.4%), fatigue (42.0% vs 38.1% and 36.8% vs 21.2%), and diarrhea (39.9% vs 30.6% and 48.5% vs 32.7%). For RIB + ET vs PBO + ET, rates of grade 3/4 febrile neutropenia ( &amp;lt;65 y, 1.2% vs 0.3%; 65- &amp;lt;75 y, 1.1% vs 0; ≥75 y, 2.9% vs 0), all grade interstitial lung disease ( &amp;lt;65 y, 1.0% vs 0.6%; 65- &amp;lt;75 y, 2.7% vs 0.7%; ≥75 y, 7.4% vs 0), and all grade QT prolongation ( &amp;lt;65 y, 9.1% vs 2.9%; 65- &amp;lt;75 y, 11.2% vs 4.1%; ≥75 y, 16.2% vs 1.9%) were numerically higher in pts 65- &amp;lt;75 y and ≥75 y than in pts &amp;lt;65 y. Rates of discontinuation due to AEs with RIB + ET vs PBO + ET were 14.6% vs 3.1% in pts &amp;lt;65 y, 19.7% vs 6.8% in pts 65- &amp;lt;75 y, and 41.2% vs 7.7% in pts ≥75 y. In pts who discontinued treatment due to AEs, the percentage of pts without prior dose reduction was 34.4% in pts &amp;lt;65 y, 40.5% in pts 65- &amp;lt;75 y, and 50.0% in pts ≥75 y. TTD in GHS was prolonged with RIB + ET vs PBO + ET in pts &amp;lt;65 y. In pts 65- &amp;lt;75 y and ≥75 y, TTD was generally similar with RIB + ET vs PBO + ET (Table). Conclusions: This pooled analysis of the MONALEESA-2, -3, and -7 trials demonstrated PFS and OS benefits with RIB + ET in elderly pts consistent with those observed in younger pts. Across age subgroups, treatment with RIB + ET also delayed TTC. Overall, RIB was well tolerated in elderly pts, with a safety profile consistent with what is anticipated for an older patient population. Additionally, there was no difference in TTD in GHS with RIB + ET vs PBO + ET in pts 65- &amp;lt;75 y and pts ≥75 y. Citation Format: Lowell Hart, Seock-Ah Im, Sara Tolaney, Mario Campone, Timothy Pluard, Berta Sousa, Gilles Freyer, Thomas Decker, Kevin Kalinsky, Astrid Thuerigen, Melissa Gao, Huilin Hu, Sherko Küemmel. Efficacy, safety, and quality of life with ribociclib + endocrine therapy in elderly patients with HR+/HER2– advanced breast cancer across the MONALEESA-2, -3, and -7 trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-01.