Albiruni R Abdul Razak, Hung-Ming Wang, Jang-Yang Chang, Myung-Ju Ahn, Pamela Munster, George Blumenschein, Benjamin Solomon, Darren Wan-Teck Lim, Ruey-Long Hong, David Pfister, Nabil F Saba, Se-Hoon Lee, Carla van Herpen, Cornelia Quadt, Douglas Bootle, Lars Blumenstein, David Demanse, Jean-Pierre Delord
{"title":"Alpelisib联合西妥昔单抗治疗复发或转移性头颈部鳞状细胞癌的1b/2期研究","authors":"Albiruni R Abdul Razak, Hung-Ming Wang, Jang-Yang Chang, Myung-Ju Ahn, Pamela Munster, George Blumenschein, Benjamin Solomon, Darren Wan-Teck Lim, Ruey-Long Hong, David Pfister, Nabil F Saba, Se-Hoon Lee, Carla van Herpen, Cornelia Quadt, Douglas Bootle, Lars Blumenstein, David Demanse, Jean-Pierre Delord","doi":"10.1007/s11523-023-00997-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models.</p><p><strong>Objectives: </strong>The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients.</p><p><strong>Patients and methods: </strong> Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC.</p><p><strong>Results: </strong>The RP2D determined for alpelisib was 300 mg/d. Alpelisib-cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69-1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30-0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49-1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months.</p><p><strong>Conclusions: </strong>The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib-cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT01602315; EudraCT 2011-006017-34.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663259/pdf/","citationCount":"0","resultStr":"{\"title\":\"A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.\",\"authors\":\"Albiruni R Abdul Razak, Hung-Ming Wang, Jang-Yang Chang, Myung-Ju Ahn, Pamela Munster, George Blumenschein, Benjamin Solomon, Darren Wan-Teck Lim, Ruey-Long Hong, David Pfister, Nabil F Saba, Se-Hoon Lee, Carla van Herpen, Cornelia Quadt, Douglas Bootle, Lars Blumenstein, David Demanse, Jean-Pierre Delord\",\"doi\":\"10.1007/s11523-023-00997-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models.</p><p><strong>Objectives: </strong>The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients.</p><p><strong>Patients and methods: </strong> Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC.</p><p><strong>Results: </strong>The RP2D determined for alpelisib was 300 mg/d. Alpelisib-cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69-1.82; P > 0.05). 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引用次数: 0
摘要
背景：在头颈部鳞状细胞癌（HNSCC）模型中，Alpelisib与西妥昔单抗联合显示出协同抗肿瘤活性。目标：推荐阶段 在一个阶段中确定2个剂量（RP2D） 1b剂量递增研究。阶段 2评估了西妥昔单抗幼稚患者的随机部分和西妥昔昔单抗耐药患者的非随机部分的抗肿瘤活性。患者和方法：在铂耐药、复发/转移性HNSCC患者中，以整片、压片混悬液或分散片混悬液的形式分28天给药 mg/d。在1b期和2期研究中，阿培利西单抗的总有效率分别为25%和9.9%，疾病控制率分别为75%和43.7%。根据中心审查，联合治疗的中位无进展生存期（PFS）为86天，西妥昔单抗单药治疗的中位数为87天（未调整HR 1.12；95% CI 0.69-1.82； P＞0.05）。当对基线协变量[来自中心数据的最长直径、血红蛋白和白细胞（WBC）的总和]进行调整时，结果有利于联合治疗（调整后的HR 0.54； 95% CI 0.30-0.97； P=0.039）。每个研究者的PFS评估导致0.76的未调整HR（95%CI 0.49-1.19； P＞0.05）有利于联合治疗。西妥昔单抗耐药患者的中位PFS为3.9个月。结论：在西妥昔单抗的基础上添加阿培利西并没有证明对患有晚期HNSCC的西妥昔mab幼稚患者的PFS有益。在西妥昔单抗耐药患者中，阿培利西单抗联合用药显示出中等活性，具有一致的安全性。临床试验注册：ClinicalTrials.gov NCT01602315；EudraCT 2011-006017-34。
A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.
Background: Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models.
Objectives: The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients.
Patients and methods: Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC.
Results: The RP2D determined for alpelisib was 300 mg/d. Alpelisib-cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69-1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30-0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49-1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months.
Conclusions: The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib-cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile.
期刊介绍：
Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes:
Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches.
Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways.
Current Opinion articles that place interesting areas in perspective.
Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations.
Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement.
Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.
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