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Publications (159)
TPS3632
Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclini...
Background
We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanis...
TPS231
Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work dem...
5
Background: For patients (pts) with colon cancer (CC), the detection of circulating tumor DNA (ctDNA) is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating recurrence risk. We hypothesized that for pts with low-risk stage II CC, a positive ctDNA status after resecti...
Purpose:
Total neoadjuvant therapy (TNT) is a newly established standard treatment for rectal adenocarcinoma. Current methods to communicate magnitudes of regression during TNT are subjective and imprecise. Magnetic resonance tumor regression grade (MR-TRG) is an existing, but rarely used, regression grading system. Prospective validation of MR-TR...
TPS3634
Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residua...
Background: The primary aim of the NRG Oncology/NSABP B-52 clinical trial was to test if estrogen deprivation (ED) administered concomitantly with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), would improve the pCR rate in patients with HER2+/ER+ early breast cancer. A numerical increase in the pCR rate was observed with E...
TPS258
Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as...
7
Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2...
TPS259
Background: Detection of circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells after surgical resection. For patients (pts) with colon cancer (CC), the detection of ctDNA is associated with persistent disease after resection and outperfo...
TPS260
Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual...
Purpose:
This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment.
Methods:
Twenty patients were enr...
Purpose
Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy.
Method
NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphami...
3564
Background: Patients (pts) with KRAS wild-type (WT) mCRC treated with single agent anti-EGFR therapy (tx) have improved OS compared to BSC but only a 10-15% response rate. Prior EGFR tx may upregulate HER amplification. For pts with quadruple WT mCRC (KRAS, NRAS, BRAF, PIC3KA), data suggest that dual targeting of the MAPK pathway, specifically...
TPS3643
Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residua...
TPS3642
Background: Detection of circulating tumor DNA (ctDNA) in patients (pts) following surgery is indicative of presence of minimal/molecular residual disease (MRD) and confers a near-certain risk of disease recurrence. Therapeutic strategies to treat MRD following standard curative therapies are needed because the risk of recurrence is high an...
TPS3647
Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as...
3569
Background: Most pts with mCRC have microsatellite stable (MSS) disease (95%) which is unresponsive to checkpoint inhibition. Chemotherapy activity is mediated through both cytotoxicity as well as immunological effects including reduced T-regulatory cell activity, enhanced tumor antigen presentation, and induced PD-L1 tumor cell expression. Ch...
Background: The NRG Oncology/NSABP B-52 neoadjuvant clinical trial was conducted to test if the addition of estrogen deprivation (ED) would improve the pCR rate in HER2+/ER+ breast cancer patients (pts) treated with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). A numerical increase in pCR rate was observed with ED (46.1% v 40.9%), but...
Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with anti-hormone therapy are highly effective treatments for oestrogen receptor positive (ER+) and HER2 negative (HER2-) advanced breast cancer. Pre-clinical and clinical studies have reported mechanisms of resistance to CDK4/6 inhibitors to include interferon signalling, h...
Background Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients (pts) with breast cancer (BC) treated with chemotherapy, human epidermal growth factor receptor 2 (HER2) targeted therapies, and endocrine therapies (ETs). Classifying tumors into intrinsic subtypes to determine optimal treatment...
140
Background: NRG Oncology/NSABP C-08 tested the efficacy of adding bev to mFOLFOX in patients (pts) with stage II or III colon cancer. In an unplanned analysis we showed that MMR status was predictive of bev benefit with dMMR pts receiving statistically significant bev benefit. More recently, we showed that immune cells and immune checkpoint pro...
TPS233
Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detec...
TPS232
Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as...
TPS212
Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying...
99
Background: Although immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design,...
Purpose:
To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2- breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers.
Experimental design:
307 postmenopausal women with ER+/HER2- primary breast cancer were r...
PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy.
METHODS: NSABP B-36 was a phase III clinical trial originally designed as a 2x2 factorial study comparing 6 cycles of FEC-100 (5-FU, epirubicin, cyclophos...
Importance:
Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed.
Objective:
To assess whether the addition of pembrolizumab during and after neoadjuv...
Background: Lapatinib (L), a HER2 signaling, tyrosine kinase inhibitor, demonstrated numerically higher pCR in NSABP B-41 when added to paclitaxel (AC→P) and trastuzumab (T) following doxorubicin + cyclophosphamide (62% v 52.5%). We previously validated an 8-gene signature that predicted the degree of T benefit in NSABP B-31 and NCCTG9831. The purp...
TPS3618
Background: The superiority of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H over chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti- epithelial growth factor receptor (EGFr) antibodies in mCRC has been demonstrated in a phase III trial (N Engl J Med 2020; 383:2207). However, more...
TPS3622
Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC,...
3516
Background: The purpose of this study was to quantify different molecules of TIME including T cells, macrophages, and immune checkpoint proteins (ICPs), and determine their association with clinical outcomes and treatment benefit in pts enrolled in C-08, which tested the efficacy of adding bev to 5-fluoruracil+leucovorin+oxaliplatin. Our pre-s...
Background: CDK4/6 inhibitors are being used in combination with aromatase inhibitors as therapy for advanced ER+ breast cancer (BC) and are being explored for use in primary BC. Few mechanisms driving resistance to added CDK4/6 inhibitors have been defined. The PALLET phase II randomized neoadjuvant trial of letrozole (LET) ± palbociclib (PALBO) i...
8
Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk pt population with correlative biomarkers. Here we report the primary and availab...
TPS148
Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, t...
TPS158
Background: Despite activity of programmed cell death-1 (PD-1) pathway inhibition in dMMR/MSI-H mCRC, approximately one-third of patients demonstrate progressive disease as best response to anti-PD1 monotherapy. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMM...
Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensi...
Purpose:
In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.
Experimental...
An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal–Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current dat...
TPS4121
Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC,...
Background: There hae been few studies of neoadjuant endocrine therapy in premenopausal (preM) women despite low pathologic complete response (pCR) rates using neoadjuant chemotherapy in ER+/HER2− pts. Suppression of Ki67, particularly complete cell cycle arrest (CCCA) defined as Ki67 <2.7% after 2 wks of neoadjuant endocrine therapy has been demon...
TPS262
Background: The majority of mCRC pts are microsatellite stable (MSS), have poor intratumoral CD8 ⁺ T cell infiltration, and no clinical response to immunotherapy checkpoint inhibitors. Preclinical studies suggest that chemotherapy may synergize with anti-PD-1. In non-small cell lung cancer (NSCLC), the combination of pembrolizumab (PemB), pe...
TPS261
Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, t...
TPS260
Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) is highly immunogenic. Preclinical data showed synergistic interactions among FOLFOX, anti-VEGF, and programmed cell death-1 (PD-1) pathway blockade. Prior phase I study of mFOLFOX6/ bevacizumab (bev) + atezolizumab (atezo) was well tolerated and enhanced intratumoral i...
TPS264
Background: Clinical improvements for locally advanced rectal cancer have been relatively static over the past few decades. While immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve th...
After the publication of this work [1] the authors have reported that in Table 3 The letter "T" in columns 5 and 7 should not be there.
Purpose:
The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker...
Background
Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for early prediction of relapse across different tumor types. In patients with colorectal cancer (CRC), multiple studies have analyzed ctDNA to monitor tumor burden using fixed gene panels and droplet digital PCR. Here, we use a highly sensitive and specific, bespoke, who...
Purpose:
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus nerat...
BACKGROUND: Colorectal cancer (CRC) pts with deficient mismatch repair (dMMR) tumors hae greater immune cell infiltration than pts with proficient (pMMR) tumors and is thought to be partly responsible for the robust response of dMMR pts to PD-1/PD-L1 blockade. Not all pts with dMMR tumors respond to PD-1 blockade. Therefore, we conducted explorator...
Background: KRAS-mt CRC has constitutively activated RAF-MEK-ERK pathways and resistance to anti-EGFR therapies. In pre-clinical models, we found that cells with inflammatory subtype tumors were sensitive to the MEK-inhibitor, MEK162, plus N, regardless of KRAS mutations. However, both KRAS-mt and -wt stem-like CRC cells were resistant to this comb...
Background: NRG Oncology/NSABP B-52 neoadjuant clinical trial was conducted to test if the addition of estrogen depriation (ED) would improe the pCR rate in HER2+/ER+ breast cancer pts treated with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). A numerical increase in the pCR rate was obsered with ED (46.1% 40.9%), but the difference w...
Background: NRG Oncology/NSABP B-52 neoadjuant clinical trial was conducted to test if the addition of estrogen depriation (ED) would improe the pCR rate in HER2+/ER+ breast cancer pts treated with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). A numerical increase in the pCR rate was obsered with ED (46.1% 40.9%), but the difference w...
Background
Monotherapy with ICB has not been effective in MSS mCRC. Preclinical data demonstrate that immunomodulators synergize with radiotherapy (RT) resulting in tumor regression at irradiated sites and rarely at non-irradiated sites. Anecdotal reports in pts have confirmed an abscopal effect of RT and ICB. This phase II, open-label, single-arm...
BACKGROUND: Colorectal cancer (CRC) pts with deficient mismatch repair (dMMR) tumors hae greater immune cell infiltration than pts with proficient (pMMR) tumors and is thought to be partly responsible for the robust response of dMMR pts to PD-1/PD-L1 blockade. Not all pts with dMMR tumors respond to PD-1 blockade. Therefore, we conducted explorator...
Background: KRAS-mt CRC has constitutively activated RAF-MEK-ERK pathways and resistance to anti-EGFR therapies. In pre-clinical models, we found that cells with inflammatory subtype tumors were sensitive to the MEK-inhibitor, MEK162, plus N, regardless of KRAS mutations. However, both KRAS-mt and -wt stem-like CRC cells were resistant to this comb...
570
Background: PALLET randomized 307 postmenopausal women with ER+ primary breast cancer to one of 4 treatment groups (3:2:2:2 ratio): A: L for 14wks; B: L for 2wks then L+P to 14wks; C: P for 2wks then L+P to 14wks; D: L+P for 14wks. This allowed a randomized 1:2 comparison of L (Group A) vs L+P (Groups B+C+D) at 14wks. P was given 125mg/d PO (21...
3503
Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA...
TPS3620
Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironm...
e15075
Background: Recent molecular subtype studies of colorectal cancer (CRC) have identified various genomic signatures. Regardless of the variety of studies, poor prognosis is associated with stem-like or mesenchymal subtypes, which are largely contributed by stromal cells or cancer-associated fibroblasts (CAF) and are driven by transforming gro...
3505
Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first...
Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer‐related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one‐third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard‐of‐care approach inc...
Background: We previously described a predictive signature for trastuzumab benefit which was validated in the adjuvant setting in an independent cohort within NSABP B-31 (the 8-gene signature) (Pogue-Geile et al JNCI, 2013) and in Alliance/NCCTG N9831 (SABCs 2017). The 8-gene signature subtyped B-31 patients into three trastuzumab benefit groups: h...
Background:
In this phase Ib study, the activity of T-DM1 plus N was assessed in patients (pt) previously treated with trastuzumab, pertuzumab, and a taxane (H+P+T). Several mechanisms of resistance have been hypothesized in pts progressing following H+P+T, including acquired alterations in the ERBB (HER) family proteins, reactivation of bypass or...
Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial col...
TPS716
Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective resp...
TPS727
Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironme...
TPS728
Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) cells are highly immunogenic. Preclinical data showed that oxaliplatin-containing chemotherapy combined with anti-VEGF enhances antitumor activity of programmed cell death-1 (PD-1) pathway blockade in murine CRC models. Prior phase I study showed mFOLFOX6/ bevacizumab (...
TPS721
Background: Locally advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers is needed to advance treatment outcomes. This NCTN multi-arm randomized phase II modular clinical trial plat...
Purpose:
CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy.
Patients and methods:
Postmenopausal women with ER-positive primary BC...
Molecular subtypes of colorectal tumors are associated with prognosis and prediction for treatment benefit from chemotherapy. The purpose of this study was two-fold: 1) to determine the association of colorectal (CRC) molecular subtypes with response to targeted therapies in pre-clinical models and 2) to identify treatments for CRC stem-like subtyp...
Cell line viability assays of inflammatory, stem-like, and TA cell lines after exposure to trametinib and neratinib.
(TIF)
CompuSyn analysis of cell line, SNU-C1, after exposure to MEK162 plus neratinib.
(TIF)
CompuSyn analysis of cell line, NCI-H747, after exposure to SCH772984 and neratinib.
(TIF)
Uncropped western blots / Raw data.
(PDF)
Cell line viability assays of TA cell lines after exposure to ERBB2 and MEK inhibitors.
(TIF)
CompuSyn analysis of cell line, NCI-H747, after exposure to MEK162 plus neratinib.
(TIF)
CompuSyn analysis of cell line, SW480, after exposure to SCH772984 and neratinib.
(TIF)
Viability assays of inflammatory and stem-like cell lines after exposure to EGFR, ERBB2, and MEK inhibitors.
(TIF)
CompuSyn analysis of cell line, SW837, after exposure to MEK162 plus neratinib.
(TIF)
CompuSyn analysis of cell line, SW1463, after exposure to MEK162 plus neratinib.
(TIF)
CompuSyn analysis of cell line, SW837, after exposure to SCH772984 and neratinib.
(TIF)
CompuSyn analysis of cell line, SW620, after exposure to SCH772984 and neratinib.
(TIF)
CompuSyn analysis of cell line, NCI-H508, after exposure to MEK162 plus neratinib.
(TIF)
Background: KRAS MT CRC tumors demonstrate constitutively activated RAF-MEK-ERK signaling pathways and resistance to anti-EGFR therapies. In preclinical studies using KRAS MT CRC cell lines, resistance to MEK inhibitors (MEKi) led to induction of ERBB3. Using kinome-centered synthetic lethality screen, suppression of ERBB3 receptor tyrosine kinase...
TPS876
Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes...
Background: The NSABP FB-7 trial, reported at SABCS 2015 (Jacobs et al., abstract # PD5-04), enrolled HER2-positive breast cancer patients (pts) with locally advanced disease who were randomly assigned to trastuzumab (T) or neratinib (N) or the combination (T+N) with weekly paclitaxel (P) followed by standard AC. Dual anti-HER2 therapy yielded grea...
Background: We have recently shown an association of colorectal tumor subtypes with differential response to chemotherapy in patients (pts), and to targeted therapy in cell lines. Pts enrolled in NSABP/NRG C-07 with stem-like tumors had a poor prognosis regardless of stage or treatment, highlighting the importance of finding new treatments for stem...
Background:
T-DM1, an antibody-drug conjugate that delivers the maytansinoid antimicrotubule agent DM1 to antigen-expressing HER2+ cells thereby improving the therapeutic index, is FDA- approved as 2nd-line therapy in HER2+ MBC patients (pts) after prior trastuzumab (T) and a taxane. Most pts currently receive T and pertuzumab (P) as neoadjuvant fo...
Background: FC-7 is a phase Ib study hypothesizing that dual ERBB blockade (neratinib and cetuximab) could overcome an acquired resistance mechanism to anti-EGFR tx in KRAS/NRAS/BRAF/PI3KCA wild type (wt) mCRC patients (pts). Previously we demonstrated a 36% rate of HER2 amp in post- anti-EGFR biopsies (bxs). Assay of plasma cfDNA is minimally inva...
TPS3629
Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy (tx) and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular...
