Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9057-9057
Author(s):  
Jonathan W. Riess ◽  
Susan G. Groshen ◽  
Karen L. Reckamp ◽  
Heather A. Wakelee ◽  
Geoffrey R. Oxnard ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Sinus Bradycardia ◽  
Clinical Activity ◽  
Recist 1.1 ◽  
Tki Resistance ◽  
Exon 20 ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki ◽  
Clinical Trial Information

9057 Background: Osi (3rd gen EGFR TKI) has robust activity in 1st line EGFR mutant NSCLC and TKI resistant T790Mpos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790Mneg, C797Xpos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) & 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790Mneg PD on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 3rd gen TKI, C) T790Mpos PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of > 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790Mneg pts with 1st/2nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790Mpos C797Spos) after PD on 3rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663. [Table: see text]

Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2581-2581 ◽  
Author(s):  
Rosario García Campelo ◽  
Enriqueta Felip ◽  
Bartomeu Massuti ◽  
Margarita Majem ◽  
Enric Carcereny ◽  
...  
Keyword(s):  
Dose Level ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

scholarly journals Protein tyrosine kinase 2: a novel therapeutic target to overcome acquired EGFR-TKI resistance in non-small cell lung cancer

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Xuexia Tong ◽  
Ryosuke Tanino ◽  
Rong Sun ◽  
Yukari Tsubata ◽  
Tamio Okimoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Protein Tyrosine Kinase ◽  
Nsclc Cell ◽  
Tyrosine Kinase 2 ◽  
Tki Resistance ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Protein Tyrosine Kinase 2

Abstract Background Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target. Methods Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC cell lines. Results PTK2 was hyperphosphorylated in PC-9/PEM. Defactinib (PTK2 inhibitor) and PD173074 (FGFR inhibitor) inhibited PTK2 phosphorylation. Combination of PTK2 inhibitor and EGFR-TKI inhibited Akt and induced apoptosis in PC-9/PEM. The combination treatment showed improved in vivo therapeutic efficacy compared to the single-agent treatments. Furthermore, erlotinib-resistant NSCLC cell lines showed PTK2 hyperphosphorylation. PTK2 inhibition in the PTK2 hyperphosphorylated erlotinib-resistant cell lines also recovered EGFR-TKI sensitivity. Conclusion PTK2 hyperphosphorylation occurs in various EGFR-TKI-resistant NSCLCs. Combination of PTK2 inhibitor and EGFR-TKI (defactinib and osimertinib) recovered EGFR-TKI sensitivity in the EGFR-TKI-resistant NSCLC. Our study result suggests that this combination therapy may be a viable option to overcome EGFR-TKI resistance in NSCLC.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8008-8008 ◽  
Author(s):  
David R. Spigel ◽  
Scott N. Gettinger ◽  
Leora Horn ◽  
Roy S. Herbst ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Human Lung Cancer ◽  
Clinical Activity ◽  
Anti Cancer ◽  
Prior Surgery ◽  
Prior Systemic Therapy ◽  
Dose Levels ◽  
Clinical Trial Information

8008 Background: Human lung cancer expresses high levels of PD-L1, which may inhibit anti-cancer immune responses. MPDL3280A, a human monoclonal Ab containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with squamous or nonsquamous NSCLC received MPDL3280A IV q3w at doses between 1-20 mg/kg in a Ph I expansion study. Pts were treated for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 53 NSCLC pts were evaluable for safety and treated at doses of ≤1 (n=2), 10 (n=10), 15 (n=19) and 20 mg/kg (n=22). Pts had a median age of 61 y (range 24-83 y), 98% were PS 0-1, 89% had prior surgery and 55% had prior radiotherapy. 98% of pts received prior systemic therapy. Pts received treatment for a median duration of 106 days (range 1-324) of MPDL3280A. The incidence of all G3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%) and fatigue (4%). No G3-5 pneumonitis or diarrhea was reported. 37 NSCLC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses were observed at dose levels between 1 and 20 mg/kg, with all responses ongoing or improving. An ORR of 24% (9/37) was observed in pts with squamous and nonsquamous histologies, including several with rapid tumor shrinkage. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). The 24-week PFS was 48%. Analysis of biomarker data from archival tumor samples demonstrated a correlation between PD-L1 status and efficacy. Pts who were PD-L1 tumor status–positive showed an ORR of 100% (4/4) and a PD rate of 0% (0/4), while pts who were PD-L1 tumor status–negative showed an ORR of 15% (4/26) and a PD rate of 58% (15/26). Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A. Clinical trial information: NCT01375842.

A phase I/II study of capecitabine combined with peginterferon alfa-2a in sorafenib-refractory advanced hepatocellular carcinoma patients.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 346-346
Author(s):  
Sadahisa Ogasawara ◽  
Tetsuhiro Chiba ◽  
Yoshihiko Ooka ◽  
Naoya Kanogawa ◽  
Tenyu Motoyama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Progressive Disease ◽  
Advanced Hepatocellular Carcinoma ◽  
Time To Progression ◽  
Recommended Dosage ◽  
Level 3 ◽  
Peginterferon Alfa ◽  
Dose Levels ◽  
Clinical Trial Information

346 Background: Several studies have demonstrated the effectiveness of combining a pyrimidine fluoride drug with interferon. Therefore, this study examined the dose of capecitabine in combination with peginterferon alfa-2a (PEG-IFN α-2a) (Phase I part) and evaluated its safety and efficacy in sorafenib-refractory advanced hepatocellular carcinoma patients (Phase II part). Methods: Capecitabine was administrated daily on days 1–14 and PEG-IFN α-2a was given on days 1, 8, and 15. The cycles were repeated every 21 days. Patients were scheduled to received capecitabine (mg/m2/day) and PEG-IFN α-2a (μg/week) at one of three dose levels in phase I: 1200/90, 1600/90, and 2000/90 (levels 1–3, respectively). Results: Thirty patients were enrolled. The recommended dose was level 3. Of the 24 patients given the drug at the recommended dosage, two (8%) showed partial responses, nine (38%) had stable disease, ten (42%) had progressive disease, and three (13%) were not evaluated. The median time to progression was 3.0 months. The most common toxicities were decreased white blood cell, neutrophil, and platelet counts, palmar-plantar erythrodysesthesia syndrome, and fatigue. Dose modification was required in ten (42%) patients. Four (17%) patients discontinued treatment because of severe adverse events. Conclusions: Capecitabine at 2000 mg/m2/day combined with PEG-IFN α-2a 90 μg/week had moderate, but manageable toxicity. Further investigation is needed to refine the efficacy. Clinical trial information: UMIN000005697.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4505-4505 ◽  
Author(s):  
Daniel C. Cho ◽  
Jeffrey Alan Sosman ◽  
Mario Sznol ◽  
Michael S. Gordon ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Study Drug ◽  
Clinical Activity ◽  
Angiogenic Therapy ◽  
Prior Surgery ◽  
Prior Systemic Therapy ◽  
Dose Levels ◽  
Receptor Antibodies ◽  
Clinical Trial Information ◽  
Anti Acetylcholine

4505 Background: Human RCC expresses PD-L1 and has been shown to respond to immune-based therapy. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with mRCC received MPDL3280A administered IV q3w at doses between 3-20 mg/kg in a Phase I expansion study. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 53 RCC pts were evaluable for safety and treated at doses of 3 (n=2), 10 (n=12), 15 (n=18) and 20 mg/kg (n=21). These pts had a median age of 62 y (range 33-79 y), 100% were PS 0-1 and all had had prior surgery. 83% of pts had received prior systemic therapy; 38% received immunotherapy, 57% received TKIs and 36% received anti-angiogenic therapy. Pts received treatment with MPDL3280A for a median duration of 190 days (range 21-317). The incidence of G3/4 AEs in RCC pts was 43%, regardless of attribution, with hypophosphatemia, fatigue, dyspnea and hyperglycemia (all 4%) being the most common. 13% of G3/4 AEs were attributable to study drug. 1 case of myasthenia gravis was observed in a pt who was retrospectively found to have anti-acetylcholine receptor antibodies prior to starting therapy. No G3-5 pneumonitis or diarrhea was reported. No treatment-related deaths occurred. 39 RCC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses, including CR, were observed across dose levels, with all responses ongoing at the time of data cutoff. Some RCC pts experienced prolonged SD prior to experiencing RECIST response. The 24-week PFS was 50%. Analysis of biomarker data from mandatory archival tumors demonstrated a correlation between PD-L1 status and efficacy. In addition, response correlated with low IL-17 expression in tumor tissue. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. PD-L1–positive status correlates with response to MPDL3280A. Durable responses have been observed in RCC pts treated with MPDL3280A and further study is warranted. Clinical trial information: NCT01375842.

RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—Preliminary findings from part 1 dose-defining phase.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8562-8562
Author(s):  
Luis G. Paz-Ares ◽  
David R. Spigel ◽  
Christoph Zielinski ◽  
Yuanbin Chen ◽  
Maria Jove ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Performance Status ◽  
Objective Response ◽  
Initial Assessment ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Primary Endpoints ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Clinical Trial Information

8562 Background: Nal-IRI is investigated as monotherapy in patients with SCLC who progressed on or after platinum regimen. The RESILIENT study is a Part 1 study of a Phase 2/3 trial to assess safety, tolerability, and efficacy of Irinotecan Liposome Injection in patients with SCLC. Methods: Nal-IRI is evaluated in patients ≥18 yrs with advanced SCLC with an ECOG performance status ≤1 and adequate organ function; prior exposure to immunotherapy is allowed. Safety and tolerability at dose levels of 85 mg/m2 and 70 mg/m2 are the primary endpoints, with assessment of exploratory efficacy signal. Results: At 24 Dec 2018 safety cutoff 12 patients in Part 1 received ≥1 dose of nal-IRI (Cohort 1 [C-1] at 85 mg/m2 dose n=4; Cohort 2 [C-2] at 70 mg/m2 dose n=8; median age 60.0 yrs; range 49–73 yrs). Three patients experienced ≥1 DLT (Cohort 1 n=3/4; Cohort 2 n=0/8). Most frequent treatment-emergent adverse events (TEAE) were gastrointestinal (GI) disorders (any grade): diarrhea (91.7%), nausea (58.3%), vomiting (41.7%), decreased appetite (58%), abdominal pain (33%) manageable by antidiarrheal regimen and antiemetics; as well as fatigue (50%) and asthenia (37.5%). Overall, hematologic toxicity was neutropenia (any grade) at 16.7% and anemia (any grade) at 16.7%. At 11 Dec 2018 efficacy cutoff the best objective response was partial response (PR) at 33.3% in 4/12 patients (C-1 n=1/4; C-2 n=3/8), median time to response was 6 wks. Overall disease control rate (DCR) was 58.3%; progressive disease (PD) was observed in 2 patients (16.7%), and 3 patients were non-evaluable (25%). Conclusions: Initial assessment suggests that nal-IRI at 70 mg/m2 dose given bi-weekly is well-tolerated and has promising antitumor activity in patients with SCLC who progressed on or after platinum regimen. Part 1 dose expansion is ongoing. Clinical trial information: NCTN03088813. [Table: see text]

scholarly journals Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells

JCI Insight ◽  
2018 ◽  
Vol 3 (24) ◽  
Author(s):  
Yuhei Kinehara ◽  
Izumi Nagatomo ◽  
Shohei Koyama ◽  
Daisuke Ito ◽  
Satoshi Nojima ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Adenocarcinoma Cells ◽  
Tki Resistance ◽  
Lung Adenocarcinoma Cells ◽  
Egfr Mutant ◽  
Egfr Tki
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