Several clinical trials have confirmed the safety and efficacy of atezolizumab (atezo; anti–PD-L1) monotherapy in advanced NSCLC, including in PD-L1–selected 1L patients (pts). Independent of PD-L1 status, high TMB is associated with atezo efficacy. Alectinib is a potent, selective ALK/RET kinase inhibitor currently approved for NSCLC pts previously treated with crizotinib and is expected to have activity in 1L NSCLC pts with ALK or RET alterations. Currently, molecular diagnostics require tumor biopsies which can be difficult to obtain. Here we present trials in progress that aim to clinically evaluate and prospectively validate novel blood-based diagnostic assays that measure TMB in the blood (bTMB) and somatic mutations (e.g., ALK/RET), and to determine the efficacy and safety of 1L atezo or alectinib in NSCLC pts.
B-F1RST (NCT02848651) is a single-arm study to evaluate the efficacy and safety of atezo and the association between bTMB and efficacy in biomarker-unselected pts. BFAST is a screening and interventional umbrella trial for pts selected based on bTMB or somatic mutations. Eligible pts must have previously untreated, stage IIIB-IVB NSCLC of any histology and measurable disease per RECIST v1.1. Pts will continue treatment until disease progression (all arms) or loss of clinical benefit (atezo only). In B-F1RST, mandatory blood samples will be prospectively collected and retrospectively tested for bTMB. In BFAST, pre-enrollment screening will identify pts who harbor oncogenic somatic mutations (ALK/RET) or are bTMB + (above a pre-specified cutoff); pts will be assigned to the appropriate cohort based on screening results. Study treatments and key endpoints are shown in the table. Additional BFAST cohorts may be added in the future to address other somatic mutations.Table:
1383TiP B-F1RST and BFAST Study Details
|Study||Treatment||Planned Enrollment, n||Primary Endpoints||Key Secondary Endpoints|
|B-F1RST Phase II||Atezo 1200 mg IV q3w||150||ORR per RECIST v1.1 (INV-assessed) for the efficacy objective Relationship between PFS per RECIST v1.1 and various bTMB quantiles for the biomarker objective||PFS and DOR per RECIST v1.1 (INV-assessed) OS|
|BFAST – Phase II/III|
|Cohort A ALK+||Alectinib 600 mg PO bid||78||ORR per RECIST v1.1 (INV-assessed)||DOR, CBR and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS|
|Cohort B RET+||Alectinib 900 mg & 1200 mg dose escalation||52-62||ORR per RECIST v1.1 (INV-assessed)||DOR, CBR and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS|
|Cohort C bTMB+||Atezo 1200 mg IV q3w or platinum-based chemotherapya||440 (R, 1:1)||PFS per RECIST v1.1 (INV-assessed)||OS PFS, ORR and DOR per RECIST v1.1 (IRF-assessed) ORR and DOR per RECIST v1.1 (INV-assessed) 6- and 12-month PFS rates|
Cisplatin or carboplatin + pemetrexed for non-squamous histology, and cisplatin or carboplatin + gemcitabine for squamous histology. Administered per standard of care. INV, investigator; IRF, independent review facility; R, randomized;b
TMB, blood Tumor Mutational Burden.
Clinical trial identification
NCT02848651, B-FAST NCT number available on poster
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
T.S.K. Mok: Spt: AZ, BI, PFE, NV, SFJ, ROG, MSD, CLVS, BMS, Eisai, Taiho ROG/GNE, LLY, NV; Stock Sanomics AB: AZ, ROG/GNE, PFE, LLY, BI, CLVS, MSD, NV, SFJ, ACEA Bio, VRTX, BMS, GeneDecode, OGX, CELG, RXDX Bod: IASLC, CLCRF, CSCO, HKCTS. S. Gadgeel: Speaker\'s bureau‐ Astra‐Zeneca, Genentech/Roche Advisory Boards‐ Astra‐Zeneca, Ariad, Pfizer, Bristol Myers‐ Squibb and Genentech/Roche. E.S. Kim: Consulting or advisory role: AstraZeneca, Celgene, BI, Eli Lily. V. Velcheti: Consulting/advisory role: Genentech, BMS, Merck, AstraZeneca, Foundation Medicine, Genoptix, Amgen. S. Hu, D.S. Shames: Genentech employee and Roche stock. T. Riehl, E. Schleifman, S. Mocci, S. Phan, M. Mathisen: Genentech employee. S.M. Paul: Genentech employee, Roche Stock, Travel, Accommodations, Expenses from Genentech. C. Yun: Employee of Genentech, Roche stock, Research funding from Genentech. M. Kowanetz: Genentech employee & Roche stock. U. Sweere: Roche employee. M.A. Socinski: Honoraria: Genentech Speakers Bureau: Genentech Research Funding: Genentech.