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Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade =3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Patients and methods: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Results: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. Conclusions: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. [ABSTRACT FROM AUTHOR]

The article discusses research on the safety, pharmacokinetics, efficacy of rociletinib in patients with non-small cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR). The study evaluated the response rate and median progression-free survival rate of patients administered with rociletinib. The researchers examined the potential toxic effects, adverse events and anti-tumor activity of the drug.

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]