Dataset Information

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

ABSTRACT: The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.

SUBMITTER: Herbst RS

PROVIDER: S-EPMC4654466 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

Herbst Roy S RS Gandara David R DR Hirsch Fred R FR Redman Mary W MW LeBlanc Michael M Mack Philip C PC Schwartz Lawrence H LH Vokes Everett E Ramalingam Suresh S SS Bradley Jeffrey D JD Sparks Dana D Zhou Yang Y Miwa Crystal C Miller Vincent A VA Yelensky Roman R Li Yali Y Allen Jeff D JD Sigal Ellen V EV Wholley David D Sigman Caroline C CC Blumenthal Gideon M GM Malik Shakun S Kelloff Gary J GJ Abrams Jeffrey S JS Blanke Charles D CD Papadimitrakopoulou Vassiliki A VA

Clinical cancer research : an official journal of the American Association for Cancer Research 20150213 7

The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of the ...[more]

PMID: 25680375

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Project description:BackgroundThe Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).MethodsLung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.FindingsBetween June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.InterpretationLung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.FundingUS National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.

Project description:Background: Immune checkpoint inhibitors have changed the treatment landscape for advanced non-small cell lung cancer. However, only a small proportion of patients experience clinical benefit from ICIs. Thus, the discovery of predictive biomarkers is urgently warranted. Evidence have shown that genetic aberrations in cancer cells can modulate the tumor immune milieu. We therefore explored the association between oncogenic mutations and efficacy to ICIs in non-squamous NSCLC. Methods: We curated genomic and clinical data of 314 non-squamous NSCLC patients receiving ICIs from four independent studies for the discovery cohort. For external validation, 305 patients from an ICI-treated cohort and 1,027 patients from two non-ICI-treated cohorts were used. Relations between oncogenic mutations and outcomes of immunotherapy were examined. Multivariate Cox regression models were applied to adjust confounding factors. Further investigation on tumor antigenicity and antitumor immunity was performed in The Cancer Genome Atlas lung adenocarcinoma cohort. Results: A total of 82 oncogenes/tumor suppressor genes according to the Oncology Knowledge base database with a frequency greater than 3% were identified and investigated in the discovery cohort. Within these genes, MGA mutations were enriched in patients with durable clinical benefit (p = 0.001, false discovery rate q < 0.05). The objective response rate was also significantly higher in patients with MGA mutation (2.63-fold, p < 0.001, FDR q < 0.05). Longer progression-free survival was found in MGA-mutated patients (HR, 0.41; 95% CI, 0.23-0.73; p = 0.003), and the association remained significant after controlling for tumor mutational burden (TMB), programmed cell death ligand-1 expression, and treatment regimens. In the validation cohort, significant improvement in overall survival was found in patients harboring MGA mutation (HR, 0.39; 95% CI, 0.17-0.88; p = 0.02). Furthermore, the survival difference was not detected in non-ICI-treated cohorts. We also demonstrated that MGA mutation correlate with higher TMB, elevated neoantigen load and DNA damage repair deficiency. Gene set enrichment analysis revealed that gene sets regarding activated immune responses were enriched in MGA-mutated tumors. Conclusion: Our work provides evidence that MGA mutation can be used as a novel predictive biomarker for ICI response in non-squamous NSCLC and merits further clinical and preclinical validation.

Project description:BACKGROUND:S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. METHODS:Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). RESULTS:Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%-17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4- 4.5 months) and 7.5 months (95% CI: 3.7-9.3 months). CONCLUSIONS:AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3-amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

Dataset Information

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

Publications

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

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