Pfizer (Italy)

Abstract Background: Vepdegestrant is an oral PROTAC ER degrader. The VERITAC-2 study (NCT05654623), the first phase 3 trial of a PROTAC, demonstrated statistically significant and clinically meaningful prolongation of progression-free survival (PFS) with vepdegestrant versus fulvestrant in patients (pts) with ER+/HER2- aBC who were previously treated with endocrine therapy (ET) and a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and had ESR1 mutations (ESR1m). Here, we report the results of prespecified subgroup analyses of PFS among pts with ESR1m. Methods: Eligible pts (aged ≥18 years) with ER+/HER2- aBC had received 1 prior line of CDK4/6i + ET, and ≤1 additional line of ET (the most recent line of ET must have been given for ≥6 months before disease progression); pts with prior chemotherapy in the metastatic setting or prior fulvestrant were excluded. Pts were randomized (1:1) to receive vepdegestrant 200 mg orally once daily or fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles; randomization was stratified by ESR1m status and the presence of visceral disease. The primary endpoint, PFS by blinded independent central review (BICR), was assessed across prespecified clinically relevant subgroups without adjustments for multiplicity. Results: In total, 270 pts with ESR1m were randomized to vepdegestrant (n=136) or fulvestrant (n=134). Across groups, the median age was 60.0 years, 21% of pts were premenopausal or perimenopausal, 80% had received prior CDK4/6i therapy for ≥12 months, 45% had liver metastases, and 42% had a PIK3CA, AKT1, or PTEN mutation at baseline. Consistent with the primary analysis, benefit was observed in PFS by BICR with vepdegestrant versus fulvestrant across all prespecified subgroups ( Table ). Conclusions: Vepdegestrant demonstrated PFS benefit compared with fulvestrant across all prespecified, clinically relevant subgroups of previously treated pts with ESR1m ER+/HER2- aBC. These analyses provide further information in key prognostic patient subgroups that may inform clinical treatment decisions for pts with ESR1m. Citation Format: E. P. Hamilton, M. De Laurentiis, K. Jhaveri, X. Hu, S. Ladoire, A. Patsouris, C. Zamagni, J. Cui, M. Cazzaniga, T. Cil, K. J. Jerzak, C. Fuentes, T. Yoshinami, A. Rodriguez-Lescure, O. Valota, D. R. Lu, M. Martignoni, S. Dychter, M. Lachowicz, X. Zhi, M. Campone. Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) [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 PD10-03.

122 Background: Most mCRC occurs in pts ≥50 y old but increasingly pts <50 y are being diagnosed with mCRC. Evidence regarding their outcomes is conflicting. BREAKWATER (Phase 3; NCT04607421) demonstrated statistically significant and clinically meaningful improvements in ORR, PFS by blinded independent central review (BICR), and OS with encorafenib + cetuximab (EC)+mFOLFOX6 vs control (chemotherapy±bevacizumab) in 1L BRAF V600E-mutant mCRC, making EC+mFOLFOX6 a new standard of care. We report analyses by age. Methods: Eligible pts with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to EC (n=158; enrollment closed after protocol amendment), EC+mFOLFOX6 (n=236), or control (n=243). Dual primary endpoints (EPs) were ORR and PFS by BICR; the key secondary EP was OS for EC+mFOLFOX6 vs control. Here, exploratory efficacy, safety, and biomarker analyses were performed by age at diagnosis (<50 y, early onset [EOCRC] or ≥50 y, average age onset [AOCRC]). A genAI tool (08/06/25; Pfizer; GPT-4o) assisted with the 1st draft; authors assume content responsibility. Results: As of Jan 6, 2025, 39, 66, and 59 EOCRC pts (~25% of each arm) were enrolled in the EC, EC+mFOLFOX6, and control arms, respectively, with 119, 170, and 184 AOCRC pts in each arm, respectively (Table). Median age (range) was 41 (24, 49) y for EOCRC pts and 64 (50, 84) y for AOCRC pts. Results for EC+mFOLFOX6 in EOCRC and AOCRC pts, respectively, were 69.7% and 64.1% for confirmed ORR by BICR, 10.9 and 14.0 mo for mPFS by BICR, and 23.8 and 30.3 mo for mOS. Results for the control arms in EOCRC and AOCRC pts, respectively, were 45.8% and 34.8% for confirmed ORR by BICR, 7.1 mo in both groups for mPFS by BICR, and 15.1 and 14.9 mo for mOS. See table for EC data. Incidence of grade 3/4 AEs was 80.0% and 82.0% for EC+mFOLFOX6, 64.8% and 67.4% for control, and 35.1% and 44.8% for EC in EOCRC and AOCRC pts, respectively. Biomarker data will be reported. Conclusions: All pts with BRAF V600E-mutant mCRC receiving 1L EC+mFOLFOX6, including EOCRC pts, showed improved ORR, PFS, and OS vs control. The safety profile of EC+mFOLFOX6 was similar for both age groups. Clinical trial information: NCT04607421 . EOCRC EOCRC EOCRC AOCRC AOCRC AOCRC EC n=39 EC+ mFOLFOX6 n=66 Control n=59 EC n=119 EC+ mFOLFOX6 n=170 Control n=184 Confirmed ORR, a % (95% CI) 56.4(41.0, 70.7) 69.7(57.8, 79.4) 45.8(33.7, 58.3) 42.0(33.5, 51.0) 64.1(56.7, 70.9) 34.8(28.3, 41.9) Odds ratio vs control (95% CI) 1.53(0.68, 3.46) 2.73(1.31, 5.68) 1.36(0.85, 2.18) 3.35(2.17, 5.18) Median PFS, a mo(95% CI) 5.4(4.2, 5.7) 10.9(9.7, 16.8) 7.1(6.7, 11.1) 8.3(6.4, 9.2) 14.0(11.3, 16.6) 7.1(5.9, 8.8) HR vs control(95% CI) 1.84(1.08, 3.13) 0.57(0.34, 0.95) 0.94(0.70, 1.27) 0.49(0.37, 0.65) Median OS, mo(95% CI) 18.9(14.6, 23.4) 23.8(21.1, NE) 15.1(13.2, 19.5) 19.5(17.6, 24.5) 30.3(21.0, NE) 14.9(13.7, 18.2) HR vs control(95% CI) 0.68(0.40, 1.16) 0.42(0.25, 0.71) 0.70(0.52, 0.95) 0.51(0.38, 0.68) NE, not estimable. a By BICR.

IntroductionGrowth hormone stimulation tests are crucial in diagnosing growth hormone deficiency (GHD) in children; however, their limited reliability and inconsistent thresholds pose diagnostic challenges. A proposed subclassification distinguishes definite GHD (dGHD), short stature unresponsive to stimulation (SUS), and idiopathic short stature (ISS). This study aims to assess whether these categories are distinguishable at baseline and differ in response to recombinant human growth hormone (rhGH) therapy, particularly in terms of near adult height (NAH) outcomes.MethodsThis retrospective cohort study analyzed data from 3,939 prepubertal children in the KIGS (Pfizer International Growth Database) who received rhGH therapy and reached NAH. Patients were classified into three groups: dGHD (GH peak <8 ng/mL with identifiable genetic, functional, or anatomical causes), SUS (GH peak <8 ng/mL without an identifiable cause), and ISS (GH peak ≥8 ng/mL). Multivariable regression analyses assessed the association of various factors with NAH outcomes.ResultsChildren with SUS showed baseline differences from those with dGHD but responded similarly to rhGH, with a height SDS increase of 0.13 for SUS and 0.12 for dGHD. In contrast, ISS children exhibited a smaller response (0 SDS increase). At the end of rhGH treatment, 74% of dGHD and SUS patients achieved a normal height (≥-2 SDS), compared to 65% of ISS patients. The most significant predictors of NAH included height at treatment initiation and mid-parental height, particularly in ISS patients.ConclusionDespite initial differences, children with SUS responded similarly to rhGH as dGHD patients, while ISS patients had a less favorable response. These findings support the importance of subclassifying short stature conditions to refine diagnostic processes, enhance treatment approaches, and improve growth outcome predictions.

ObjectiveWith 5 years of follow-up in the phase 3 CROWN study, lorlatinib showed unprecedented improvement in progression-free survival coupled with prolonged intracranial efficacy in patients with ALK-positive metastatic non-small cell lung cancer (mNSCLC). Here, we report kinetics and mitigation practices of select adverse events (AEs) to inform therapy management strategies.DesignPost hoc safety analyses from the CROWN study assessed the incidence, prevalence, time to onset, duration, management, and resolution of hyperlipidemia, edema, weight gain, central nervous system (CNS) AEs, and peripheral neuropathy in the lorlatinib group (n = 149).ResultsAfter 5 years of follow-up, no new safety signals were observed. All-cause any-grade and grade 3/4 AEs occurred in 100% and 77% of patients, respectively; AEs led to lorlatinib dose reduction in 23% of patients, dose interruption in 62%, and permanent discontinuation in 11%. The median time to onset of any-grade hyperlipidemia was 0.5 months; 71% of events were managed with lipid-lowering agents. Median time to onset of any-grade edema, weight gain, CNS AEs, and peripheral neuropathy ranged from 2 to 4 months. Most weight gain events (95%) were mitigated with lifestyle modifications. Incidence and prevalence of CNS AEs did not increase over time; 58% of events did not require medical intervention.Conclusions and RelevanceThis post hoc analysis suggests that with longer lorlatinib exposure, no new safety signals emerged, and treatment discontinuation due to AEs remained low after 5 years of follow-up. Most AEs were effectively managed with dose modifications, indicating that current management strategies can be effective to mitigate toxicity. ClinicalTrials.gov NCT03052608

Rebound of coronavirus disease 2019 (COVID-19) is defined as return of symptoms and/or viral positivity after resolution of the initial infection. While rebound is typically mildly symptomatic and rarely associated with progression to severe disease, the benefit of repeated antiviral treatment has not been investigated. This randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of a second 5-day treatment course of nirmatrelvir/ritonavir versus placebo/ritonavir in participants with symptomatic mild to moderate COVID-19 with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid antigen test within 14 days of initial nirmatrelvir/ritonavir treatment. The primary efficacy endpoint was the change in viral SARS-CoV-2 RNA level from baseline to Day 5. The full analysis set included 436 participants assigned to treatment (292, nirmatrelvir/ritonavir; 144, placebo/ritonavir). A second 5-day course of nirmatrelvir/ritonavir resulted in a significant reduction in viral RNA levels at Day 5 compared with placebo/ritonavir (P = .0004; 95% CI, -1.09, -.32). The median time to 2 consecutive negative RAT results was 4 versus 5 days, and the median time to sustained alleviation of all targeted signs/symptoms was 8 versus 9 days in the nirmatrelvir/ritonavir and placebo/ritonavir groups, respectively. Retreatment with nirmatrelvir/ritonavir was safe and well tolerated, and there were no occurrences of COVID-19-related hospitalizations or deaths. A repeated 5-day course of nirmatrelvir/ritonavir was safe and well tolerated and was associated with a faster decline in viral RNA levels. In this study, there was no clear benefit of retreatment because rebound was transient and mild and did not lead to severe COVID-19. NCT05567952; https://clinicaltrials.gov/study/NCT05567952.

Objective: This study aimed to estimate the cost-effectiveness of nirmatrelvir/ritonavir (NMV/r) versus the standard of care (SoC) for patients with mild-to-moderate coronavirus disease 2019 (COVID-19) at high risk for progression to severe illness from the perspective of the Italian National Health Service.Methods: A cost-effectiveness model was developed using a closed cohort of 1,000 infected patients. It employeda short-term decision tree (1 year) followed by a lifetime 2-state Markov model (alive and dead). Theshort-term decision tree captured costs and outcomes associated with the primary infection and healthcare utilization; survivors of the short-term decision tree were followed until death to calculate Italian quality-adjustedlife years (QALYs), adjusted in the short-term for survivors to mechanical ventilation. Baseline hospitalization rateand NMV/r effectiveness were sourced from the Istituto Superiore di Sanità (ISS) and the randomized clinical trialEvaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR), respectively. Other inputs weregiven by previous COVID-19 studies and publicly available sources. Sensitivity analyses were conducted for allmodel inputs to test the robustness of the results of the model.Results: NMV/r presented an advantageous cost-effectiveness ratio of 2,237 €/QALY, compared to the SoC, in thelong-term horizon (30 years). Results were most sensitive to baseline risk of hospitalization and NMV/r treatmenteffectiveness parameters. The probabilistic analysis indicated that NMV/r has a 100% probability of being costeffective at a 33,004 € willingness-to-pay threshold.Conclusions: From the Italian National Health Service perspective, NMV/r is cost-effective compared to the standard of care for patients at high risk for severe COVID-19.