LBA2TATTON expansion cohorts: A phase Ib study of osimertinib plus savolitinib in patients (pts) with EGFR-mutant, MET-positive NSCLC following disease progression on a prior EGFR-TKI.

Background Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that adding savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET TKI, to osimertinib, a 3rd generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which selectively inhibits EGFR TKI sensitising (EGFRm) and T790M resistance mutations, may overcome MET-driven resistance to EGFR TKIs. We present updated data from TATTON Part B and data from Part D, for the first time. Methods Pts were ≥18 years (Japan ≥20 years), mainly Asian, with locally advanced/metastatic, MET-positive, EGFRm NSCLC and disease progression on prior therapy. Pts enrolled based on MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥ 50% of tumour cells), with retrospective central confirmation. Pts in Part B received osimertinib 80 mg + savolitinib 600 mg or 300 mg orally (PO) once daily (QD). Pts in Part D received osimertinib 80 mg + savolitinib 300 mg PO QD, were T790M negative and had received no prior 3rd generation EGFR TKI. Primary endpoints: safety and tolerability; secondary endpoints included objective response rate and progression-free survival. Results In Parts B (N = 138) and D (N = 42); Grade ≥3 AEs reported by 57% and 38%, respectively; serious AEs reported by 45% and 26%, respectively. AEs possibly related to treatment, led to discontinuation of savolitinib in 38 (28%) vs 9 (21%) and osimertinib in 14 (10%) vs 2 (5%), for Parts B and D, respectively. Efficacy data: Table. Table: LBA2 Efficacy endpoints   Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)    Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)  * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Table: LBA2 Efficacy endpoints   Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)    Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)  * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Conclusions Our results support that osimertinib + savolitinib may overcome MET-driven resistance to EGFR TKIs, and warrant further exploration of the osimertinib 80 mg + savolitinib 300 mg combination in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. Clinical trial identification NCT02143466. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Research grant / Funding (self): ONO; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Takeda. L.V. Sequist: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Janssen; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merrimack Pharmaceuticals; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): LOXO; Honoraria (self), Research grant / Funding (institution): Blueprint Medicines; Honoraria (self), Research grant / Funding (institution): Genentech. M. Ahn: Honoraria (self), Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche; Advisory / Consultancy: Takeda, Alpha Pharmaceutical. B.C. Cho: Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics; Licensing / Royalties, Patent with royalties paid: Champions Oncology. H. Yu: Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, Astellas. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.C. Yang: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, Ono Pharmaceuticals; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, Blueprint. M. Cantarini: Shareholder / Stockholder / Stock options, Full / Part-time employment, Full time Contractor: AstraZeneca. R.B. Verheijen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Aduro Biotech. A. Mellemgaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Frewer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. X. Ou: Full / Part-time employment, Full time Contractor: AstraZeneca. G. Oxnard: Honoraria (self): Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, Foundation Medicine; Advisory / Consultancy: AstraZeneca, Inviata, Takeda, Loxo, Ignyta, DropWorks, GRAIL, Illumina, Janssen; Licensing / Royalties, Patent pending: DFCI. [ABSTRACT FROM AUTHOR]