We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants ...yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
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•ERBB2 mutations occur in at least 25 tumor types with varying patterns of mutations•Mutation-induced changes in drug-binding pocket volume dictate drug sensitivity•Poziotinib inhibits mutant HER2, yielding a 42% response rate in NSCLC patients•Combination of poziotinib with T-DM1 potentiates antitumor activity of both agents
Robichaux et al. show that ERBB2 mutation hotspots vary across human tumor types, which affect the volume of the HER2 TKI binding pocket and dictate drug sensitivity. Poziotinib is the most potent HER2 TKI among those tested. Moreover, poziotinib enhances T-DM1 efficacy by increasing the cell-surface HER2 level.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We characterized the landscape and drug sensitivity of
ERBB2
(
HER2
) mutations in cancers. In eleven datasets (n = 211,726),
ERBB2
mutational hotspots varied across 25 tumor types. Common HER2 ...mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs)
in vitro
, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in
ERBB2
exon 20-mutant NSCLC resulted in a confirmed objective response rate of 42% in the first twelve evaluable patients. In preclinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regressions with combination treatment.
Robichaux et al. show that
ERBB2
mutation hotspots vary across human tumor types, which affect the volume of the HER2 TKI binding pocket and dictate drug sensitivity. Poziotinib is the most potent HER2 TKI among those tested. Moreover, poziotinib enhances T-DM1 efficacy by increasing the cell surface HER2 level.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
HER2 is mutated in ~3% of NSCLC cases, with most of these mutations occurring within exon 20. HER2 TKIs including afatinib and dacomitinib have objective response rates <30% in NSCLC. We ...have shown that EGFR exon 20 insertions stabilize the active confirmation, and restrict the size of the ATP pocket; and the small, flexible TKI, poziotinib, potently inhibits EGFR exon 20 insertions. Therefore, we hypothesized that HER2 exon 20 insertions induce similar changes, resulting in limited activity of EGFR/HER2 TKIs; and exon 20 HER2 mutations can be targeted with small, flexible covalent TKIs. To this end, Ba/F3 cells expressing 8 different HER2 exon 20 mutations were generated and screened against TKIs including erlotinib, lapatinib, afatinib, dacomitinib, neratinib, poziotinib, osimertinib and others. In Ba/F3 cells with HER2 exon 20 mutations, 1st and 3rd generation TKIs failed to inhibit cell (IC50 values >115nM). While 2nd generation TKIs had some activity (average IC50 =11nM), poziotinib significantly inhibited the growth of all HER2 exon 20 mutations tested with an average IC50 value of 1.9nM. 3D modeling revealed that HER2 exon 20 insertions induce conformational changes which cause constitutive activation and steric hindrance of C805 reducing the ability of larger TKIs to covalently bind. Therefore the smaller flexible terminal group of poziotinib can overcome the structural changes induced by exon 20 insertions. To test this in vivo HER2 A775insYVMA GEMMs were treated daily with poziotinib. Treatment reduced tumor burden by 60% at 4 weeks and had a durable response of 322 days. Based on preclinical data, a heavily pre-treated patient with HER2 driven NSCLC (HER2 A771insAYVM) was placed on a compassionate use protocol and received 16mg poziotinib daily. After 4 weeks, the patient experienced a significant radiological response with reduction in FDG avidity in the left 7th rib, right sacrum and a right lower lobe nodule among others. Moreover, HER2 A771insAYVM circulating free DNA dropped from 2.4% to <0.3%. Finally the frequency and sensitivity of HER2 exon 20 mutations in other cancers has not been fully characterized. To this end we have examined HER2 mutations across patients treated at MD Anderson Cancer Center. HER2 exon 20 mutations were found to occur in breast, endometrial, esophageal, small intestine, colorectal, melanoma and other cancers. In vitro testing of many of these mutations confirms their sensitivity to poziotinib. Collectively, these preclinical and clinical data indicate that poziotinib is a potent, clinically active inhibitor of HER2 exon 20 mutant-driven cancers. Based on these findings and the preclinical and clinical activity of poziotinib in EGFR exon 20 mutants, two phase II clinical studies of poziotinib in EGFR and HER2 exon 20 mutant NSCLC are currently ongoing and a basket trial for other HER2 and EGFR exon 20 mutant cancers is in development.
Citation Format: Jacqulyne P. Robichaux, Yasir Y. Elamin, Zhi Tan, Marelo Vailati Negrao, Mark Routbort, Brent Roeck, Shuai Li, Shengwu Liu, Ting Chen, Jordi Rodon Ahnert, Lixia Diao, Monique B. Nilsson, Shuxing Zhang, Zane Yang, Jing Wang, Funda Meric-Bernstam, Kwok-Kin Wong, John V. Heymach. Poziotinib overcomes de novo resistance of HER2 exon 20 mutations in NSCLC and other cancers: Preclinical studies and initial clinical testing abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4772.
SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. ...Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of >50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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