|
|
- F. André
- V. Guarneri
237O - A phase II trial of pan-HER inhibitor Poziotinib, in patients with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed regimens: The results of NOV120101-203 trial (ID 3479)
- Y. Park
Abstract
Background
Although the introduction of HER2 directed therapy including trastuzumab, pertuzumab, lapatinib, and TDM-1 in the treatment of HER2-positive metastatic breast cancer (mBC) patients favorably changed the natural history of this disease, HER2-positive mBC will eventually progress in most patients. Poziotinib is a novel, oral pan-HER kinase inhibitor which showed potent anti-tumor activities through irreversible inhibition of HER family tyrosine kinases.
Background
Although the introduction of HER2 directed therapy including trastuzumab, pertuzumab, lapatinib, and TDM-1 in the treatment of HER2-positive metastatic breast cancer (mBC) patients favorably changed the natural history of this disease, HER2-positive mBC will eventually progress in most patients. Poziotinib is a novel, oral pan-HER kinase inhibitor which showed potent anti-tumor activities through irreversible inhibition of HER family tyrosine kinases.
Trial design
This open-label, multicenter phase 2 study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive breast cancer. Patients with HER2-positive metastatic breast cancer who have progressed from ≥2 HER2-directed therapies were enrolled in the study. Patients received poziotinib 12 mg once daily on a 14-day on/7-day off schedule . Dose increases up to 16 mg or decreases to 8-10 mg were allowed at appropriate time points based on safety and efficacy assessments. The primary efficacy endpoint of the trial is Progression-Free Survival (PFS). Key secondary endpoints are Objective Response Rate (ORR), Overall Survival (OS), and safety.
Methods
This open-label, multicenter phase 2 study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who have progressed from more than 2 HER2-directed therapies. Patients received poziotinib 12 mg once daily on a 14-day on/7-day off schedule. Dose escalation up to 16 mg was allowed at appropriate time point and dose reduction to 8-10 mg were performed according to toxicities. Progression-free survival (PFS) as the primary endpoint and objective response rate (ORR), overall survival (OS), and safety were evaluated.
Clinical trial identification
NCT02418689
Results
From Apr 2015 to Feb 2016, 106 patients were enrolled in the trial from 7 institutes in Korea. The patients were median age of 50 (range: 30∼76) who had received median 4 prior anti-cancer therapies including median 2 HER2-directed therapies in the advanced or metastatic setting. Median follow up duration was 12 months. The median PFS was 4.04 months (95% CI, 2.94 - 4.40 months), and median overall survival has not been reached. The disease control rate was 75.49% (77/102) including 20 patients with confirmed partial response. The most common treatment-related AEs were (total/grade≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%), and rash (63.21%/3.77%).
Conclusions
Poziotinib showed meaningful clinical activity in heavily-treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities leading to dose modification. Biomarker study being analyzed from pre- and on-treatment biopsies is warranted to support further on the meaningful clinical outcomes of poziotinib in HER2-positive mBC.
Clinical trial identification
NCT02418689
Legal entity responsible for the study
National OncoVenture & Hanmi Pharmaceutical Co., Ltd.
Funding
Hanmi Pharmaceutical Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.
217O - A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with anthracycline-based neoadjuvant chemotherapy (ID 2847)
- C. Criscitiello
Abstract
Background
The extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after anthracycline-based neoadjuvant chemotherapy (NACT) is associated with a better prognosis, in patients with triple-negative breast cancer (TNBC). We aimed to develop a genomic signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival.
Methods
Using 99 pre-treatment samples (training set), we generated a four-gene signature that predicts post-NACT TILs using the LASSO technique. Prognostic value of the signature on survival was first assessed on the training set (n = 99) and then evaluated on an independent validation set including 185 patients with TNBC treated with NACT.
Results
A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 predicted the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, a one-unit increase in the signature value was associated with distant-relapse free survival (DRFS) (HR: 0.28, 95%CI: 0.13-0.63, p = 0.0018). For the validation dataset, the four-gene signature was significantly associated with DRFS in the entire set (HR: 0.26, 95%CI: 0.11-0.59, p = 0.0012) and in the subset of patients with residual disease (HR: 0.23, 95%CI: 0.10-0.55, p = 0.0008).
Conclusions
We developed a four-gene signature of immune-activation, which predicts outcome in patients treated with NACT for TNBC.
Legal entity responsible for the study
Carmen Criscitiello
Funding
Transcan-2011, Operation Parrain Chercheurs, Odyssea, Fondation Dassault.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 237O and 217O (ID 5705)
- V. Guarneri
LBA13 - Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086 (ID 3756)
- S. Loi
Abstract
Background
TILs have been observed in TNBC and are thought to represent pre-existing antitumor immunity. Thus, TILs could be a biomarker for response to immune checkpoint blockade. We assessed if TIL levels were associated with response to pembro monotherapy in the phase 2 KEYNOTE-086 study of previously treated mTNBC of any PD-L1 expression (cohort A) or previously untreated, PD-L1–positive mTNBC (cohort B) (NCT02447003).
Methods
Stromal TILs were quantified by a single pathologist blinded to clinical data using a published method of light microscopy of H&E-stained slides obtained from tumor biopsies. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx. Response was assessed every 9 wk for 12 mo, then every 12 wk (RECIST v1.1, central review). Relationships between transformed TIL levels and ORR and DCR (CR + PR + SD ≥ 24 wk) were assessed using logistic regression adjusted for cohort (A vs B) and biopsy site (lymph node vs non-lymph node). All P values are 1 sided.
Results
193 of the first 222 patients (pts) enrolled had evaluable tumor samples: 147 from cohort A, 46 from cohort B; 146 samples were newly collected (mostly from metastatic sites), 47 were archival (mostly from primary breast tumors). Median [IQR] TIL level was higher in cohort B vs A (17.5% [6.2-57.5%] vs 5% [1-10%], Wilcoxon rank sum P < .001), and in archival vs newly collected samples (10% [5-40%] vs 5% [1.2-15%], P < .001), and lymph node vs non-lymph node samples (10% [5-50%] vs 5% [2-15%], P = .01). ORR in pts with TIL level ≥ vs < median was 6% vs 2% in cohort A and 39% vs 9% in cohort B. Median (IQR) TIL level in responders vs nonresponders was 10% (7.5-25%) vs 5% (1-10%) in cohort A and 50% (5-70%) vs 15% (5-37.5%) in cohort B. In the combined cohorts, higher TIL levels were associated with significantly improved ORR (odds ratio 1.26, 95% CI 1.03- 1.55, P = .01) and DCR (odds ratio 1.22, 95% CI 1.02-1.46, P = .01). Area under the ROC curve was 0.75 for ORR and 0.69 for DCR. PD-L1 expression significantly correlated with TIL levels (ρ = 0.4962, P < .001).
Conclusions
TIL levels can identify pts with mTNBC with a greater chance of achieving response to pembro monotherapy, particularly in the first-line setting.
Clinical trial identification
ClinicalTrials.gov number NCT02447003, originally posted May 14, 2015, KEYNOTE-086; EudraCT number 2015-000294-13, originally entered April 4, 2015
Legal entity responsible for the study
Merck & Co., Inc.
Funding
Merck & Co., Inc.
Disclosure
S. Loi: Institution receives funding from Merck & Co., Inc. S. Adams: Study funding to the institution from Merck & Co., Inc. P. Schmid: Consulting or advisory role: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Genentech/Roche, Merck & Co., Inc., Novartis, Pfizer, Puma Biotechnology; research funding (all to institution): Astellas Pharma, AstraZeneca, Genentech, Medivation, Novartis, Oncogenex. J. Cortés: Stock (self): MedSIR; honoraria (self): Roche, Novartis, Eisai, Celgene, Pfizer; consulting or advisory role (self): Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera Pharmaceutical. D.W. Cescon: Funds to institution for clinical trials: Merck & Co., Inc. E.P. Winer: Consulting fees: Genentech, Leap, Tesaro; research funding: Genentech, Merck & Co., Inc. D.L. Toppmeyer: Prof. Toppmeyer reports salary and stock options (husband): Novartis; consulting fees (self): Merck & Co., Inc., Novartis. H.S. Rugo: Funds to institution for contracted research: Merck & Co., Inc., Eli Lilly, Novartis, Pfizer, OBI, Macrogenics, Eisai, Roche. M. De Laurentiis: Advisory board member: Amgen, AstraZeneca, Cengene, Ipsen, Novartis, Pfizer, Roche; speakers\' bureau: Novartis, Pfizer, Roche; research funding: Roche; Honoraria: Amgen, AstraZeneca, Cengene, Ipsen, Novartis, Pfizer, Roche. R. Nanda: Advisory board member: AstraZeneca, Genentech, Merck & Co., Inc., Peregrine, Pfizer, Puma, Syndax; Research funding: Celgene, Corcept Therapeutics, Merck & Co., Inc.; Other (DSMB member): G1 Therapeutics. A. Tan: Research funding to the insitution from Merck & Co., Inc. A. Wang: Salary: Merck & Co., Inc. G. Aktan, V. Karantza: Salary and stock options: Merck & Co., Inc. R. Salgado: Advisory board member: Roche; Research funding: Puma; Travel expenses: Roche. All other authors have declared no conflicts of interest.
LBA14 - Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple negative breast cancer: TONIC-trial (ID 5228)
- M. Kok
Abstract
Background
Anti-PD(L)1 can result in durable responses in patients with metastatic triple negative breast cancer (TNBC). However, only a small subgroup of TNBC patients benefit from anti-PD(L)1 with response rates of ± 10% in unselected cohorts. As such, there is an urgent clinical need to identify strategies that render the tumor micro-environment more sensitive to anti-PD(L)1. Preclinical studies have shown that irradiation or low dose chemotherapy may stimulate anti-cancer immune responses. Here we present the first results of a phase II randomized trial of nivolumab after short induction with irradiation or low dose chemotherapy in metastatic TNBC.
Methods
Fifty patients with metastatic TNBC who received ≤ 3 lines of palliative chemotherapy were randomly allocated to one of five 2-week induction treatments consisting of 1) 3x8 Gy irradiation of one metastatic lesion or 2) 2x doxorubicin 15mg weekly or 3) cyclophosphamide 50mg daily orally or 4) 2x cisplatin 40mg/m2, weekly or 5) no induction treatment. After this 2-week induction period, all patients received nivolumab 3mg/kg until RECIST 1.1 progression. After 5x10 evaluable patients with paired biopsies (stage I), arms will be closed according to a ‘pick the winner’ concept (Simon’s two-stage design).
Results
To date, 50 patients are evaluable according to RECIST 1.1 with a median follow-up of 4 months (range 1-15). Previous treatments for metastatic disease were 0, 1 or 2+ lines in 20%, 52% and 28%, respectively. The ORR is 22% with 2 CRs (4%) and 9 PRs (18%). Additional two patients had a SD (4%), resulting in a clinical benefit rate (CR+PR+SD>24weeks) of 26%. The median duration of response was 10.9 months (95% CI 7.1-NA). Changes in tumor-infiltrating lymphocytes (TIL) after irradiation or low dose chemotherapy as well as response rates per treatment arm will be presented at the meeting.
Conclusions
This first study in TNBC shows that nivolumab after priming the tumor micro-environment with either irradiation or chemotherapy is feasible and results in a promising response rate that appear higher than expected based on previous PD-1/PD-L1 blockade monotherapy studies in unselected TNBC.
Clinical trial identification
Eudract number: 2015-001969-49
Legal entity responsible for the study
Netherlands Cancer Institute
Funding
Dutch Cancer Society, Pink Ribbon, BMS
Disclosure
D. Cullen: D. Cullen is an employee of BMS. R. Salgado: travel support Roche. T.N.M. Schumacher: Stocks Kite pharma, NEON, AIMM therapeutics Employee Kite pharma C.U. Blank: prof Blank is member of the advisory board of BMS. S.C. Linn: Advisory role: Novartis, Cergentis, Philips, AstraZeneca, Roche, Genentech, IBM. All other authors have declared no conflicts of interest.
Invited Discussant LBA13 and LBA14 (ID 5708)
- G. Curigliano