Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol

Abstract

Background: The 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).

Methods: Lung-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.

Findings: Between 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.

Interpretation: Lung-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.

Funding: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.

Figure 1.. Lung-MAP (S1400) Screening Registrations, Assignments, and Sub-study Registrations Summary

Footnotes: # The sub-study assignment process differed for pre-screened patients and screened at progression patients. Only patients who had successful biomarker screening were assigned to sub-studies. Pre-screened patients were assigned to a sub-study upon notification by the site that the patient had progressed on their prior therapy. If the notice was never submitted, the patient would not have received a sub-study assignment. Patients screened at progression received their sub-study assignment as soon as the biomarker results were available. *See Tables 2 and S7 for sub-study descriptions. S1400A evaluated durvalumab in anti-PD-(L)1-naïve squamous cell carcinoma (SCCA); S1400B evaluated taselisib for PI3KCA-positive SCCA; S1400C evaluated palbociclib in SCCA with cell cycle gene alterations; S1400E evaluated rilotumumab + erlotinib in c-MET positive SCCA; S1400F evaluated durvalumab + tremelimumab in ICI-relapsed/refractory SCCA; S1400G evaluated talazoparib in homologous recombinant repair deficiency positive SCCA; S1400I evaluated nivolumab + ipilimumab versus nivolumab in ICI-naïve SCCA; S1400K evaluated ABBV-399 in c-MET positive SCCA. The S1400 protocol was active between June 16, 2014 and January 28, 2019. Simultaneous with the closure of S1400, a new screening protocol called LUNGMAP was opened. Accrual to sub-studies activated under LUNGMAP as listed under that name. 1a-3b: See Appendix page 1 for reasons.

Figure 2.. Timelines for Sub-studies, Activation, Design and Eligibility Changes for S1400

Footnotes: v. = versus. CCGA = cell cycle gene alterations; HRRD = homologous recombinant repair deficiency. S1400E therapies were: rilotumumab + erlotinib v. erlotinib. See Tables 2 and S7 for full sub-study descriptions.

Figure 3.

Overall Survival from Time of Sub-study Assignment by Screening Type

Figure 4.. Overall Survival from Time of Sub-study Registration for Molecular Targeted Therapies, Immunotherapies and Chemotherapy

A: Progression-free Survival from the Time of Sub-study Registration by Treatment Type B: Overall Survival from the Time of Sub-study Registration by Treatment Type