Search

Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients with advanced EGFR -mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25–75 mg p.o. twice a day; continuous or intermittent), savolitinib (600–800 mg p.o. once a day), or durvalumab (3–10 mg/kg intravenous every 2 weeks). At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm—diarrhea (75%), rash (58%), nausea (47%); savolitinib arm—nausea (67%), rash (56%), vomiting (50%); durvalumab arm—rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. NCT02143466. • Patients with advanced EGFR -mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab. • Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib. • Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease. • Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified. • Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes. [ABSTRACT FROM AUTHOR]

Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. This analysis included patients with treatment-naive, EGFR -mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR -mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR- mutant advanced NSCLC. [Display omitted] • Amivantamab-lazertinib significantly improved PFS in patients with detectable ctDNA at baseline versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients without ctDNA clearance at C3D1 versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with TP53 co-mutations versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with liver metastases versus osimertinib. • Eighty-nine percent of patients with analyzable ctDNA by NGS from MARIPOSA had at least one high-risk baseline feature. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR -mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. Safety was assessed in patients with EGFR -mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. In patients with EGFR -mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy. • The phase I U31402-A-U102 study evaluated HER3-DXd in heavily pretreated patients with EGFR -mutated NSCLC. • Ninety-seven patients previously treated with EGFR TKI and PBC received HER3-DXd 5.6 mg/kg intravenously every 3 weeks. • Responses were seen across the range of HER3 expression and across diverse mechanisms of resistance to EGFR TKI therapy. • Acquired mutations in ERBB3 were characterized. • OS was 15.8 months (95% CI 10.8-21.5 months). [ABSTRACT FROM AUTHOR]

Background: The IPASS study reported that gefitinib provided superior progression-free survival (PFS) compared with carboplatin and paclitaxel in a clinically selected lung cancer patient population; the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumours because patients with wild-type (WT) tumours had inferior outcomes. The current study compared PFS for pemetrexed plus cisplatin induction therapy followed by gefitinib as maintenance therapy versus gefitinib monotherapy as first-line treatments in patients with non-squamous non-small cell lung cancer. Methods: Patients (n=236) with unknown EGFR mutation status were randomised 1:1 to pemetrexed plus cisplatin for six cycles or gefitinib. Patients without progressive disease after six cycles received gefitinib maintenance therapy. Primary endpoint analysis (Wilcoxon test after 169 PFS events) provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples were analysed for EGFR mutation status. Findings: Baseline characteristics were balanced across treatment arms. 50 (68%) of 74 samples had mutations. Primary PFS analysis showed no significant difference between treatment arms (Wilcoxon p= 0.217). Unadjusted HR was 0.85 (95% confidence interval [CI] 0.63-1.13). During most of the study, the Kaplain Meier curve for pemetrexed plus cisplatin remained above the curve for gefitinib. In a prespecified subgroup analysis, EGFR-by-treatment interaction as statistically significant (p=0.008), showing treatment effect significantly differed by EGFR status. The PFS HR favoured pemetrexed plus cisplatin in EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients (EGFR-mutated: HR 0.83 [95% CI 0.42-1.62], p=0.585; EGFR-WT: HR 0.18 [95% CI 0.06-0.51], p=0.001). HRs for intention to treat (ITT) and EGFR-mutated patients were not constant and should be interpreted with caution. Interpretation: In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, EGFR-WT patients did not benefit from front-line EGFR tyrosine kinase inhibitor treatment. Identification of EGFR mutational status is key for management of advanced non-squamous non-small cell lung cancer. [ABSTRACT FROM AUTHOR]