Forero, Andres

e14537 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral, pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d) and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI/EORTC, 2005; James, ASCO, 2006 and Saleh, ASCO, 2007). MTD in the QD schedule has been previously reported. In this study different dosing schedules of AT-101 were tested in adults with advanced cancers and final results for the pulse dosing schedule of twice a day for three days every other week (b.i.d. x 3d EOW) are being reported. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses of 30–80 mg b.i.d. x 3d EOW. Adverse events (AEs) were graded by the NCI CTCAE v3.0. Efficacy was determined by RECIST. Results: 37 pts have been enrolled. Safety data is available on 34/37 pts. In this b.i.d. x 3d EOW dosing schedule, ileus/small bowel obstruction (SBO) occurred in 3 pts (one at each dose level of 30, 40 and 50 mg) and was the dose limiting toxicity for this schedule. Of note, the SBO that occurred at 30 mg was felt to be unrelated to study agent therefore, 30 mg b.i.d. x 3d EOW was the MTD determined for this schedule. The most common (>50%) grade 1–2 AEs included: nausea, vomiting, diarrhea, fatigue and anorexia. Grade 3–4 AEs occurring in > 2 pts include: nausea, abdominal pain, elevated AST (3 pts each), vomiting, fatigue, dehydration (4 pts each), hypokalemia (5 pts). Stable disease was reported in 13/37 (35%) pts. One pt with NSCLC continues on study with stable disease for 33 cycles and 2 additional pts were on study with stable disease for 18 and 9 cycles. The mean Plasma Cmax was 301 ng/ml (+ 477 ng/ml SD) and mean AUC for 30 mg b.i.d.x3d EOW was 1080 ng*hr/ml (+ 1990 ng/ml SD) with a median peak concentration at 4 hours post dose. Conclusions: Pulse dosing of AT-101 achieved an MTD of 30mg b.i.d. x 3d EOW and is associated with reduced toxicity than continuous daily dosing, and may be preferable in combination regimens. [Table: see text]

3583 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d), and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI_EORTC, 2005; James, ASCO, 2006). Our ongoing Phase 1 study tests different dosing schedules of AT-101 in adults with advanced cancers. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses twice a day for three days every other week (BIDx3dEOW) or once weekly (QW). Adverse events (AEs) were graded by the NCI CTCAE v. 3.0. Results: 24 pts have received pulse dosing; safety data are available for 20 pts (30–70 mg BIDx3dEOW, N=13; 80–160 mg QW, N=7). For comparison, 38 pts received 5–60 mg QD. Median number of cycles (range): BIDx3dEOW_2(1–9); QW_3(1–3), QD_2(1–12). AST/ALT is not yet dose limiting, nor the MTD reached, at 70 mg BIDx3dEOW or 160 mg QW. Ileus occurred in 4/38 pts dosed daily but in no pts on either pulse schedule. Other potentially related Gr 3–4 AEs were: BIDx3dEOW (6 pts)–AST (1 pt), abdominal pain (2 pts), elevated CK/right ventricular dysfunction (1 pt w/history of COPD/doxil therapy), hypokalemia (1 pt);QW: none; QD: AST/ALT (5 pts), nausea/vomiting/diarrhea (3 pts each) fatigue (2 pts), hypocalcemia (2 pts), hypokalaemia/anorexia/dehydration/hypophosphatemia (1 pt), elevated GGT (1 pt). The most common Gr 1–2 AEs_nausea/vomiting/fatigue_occurred in over 50% of QD and BIDx3dEOW pts but only 1/7 QW pts. Plasma Cmax (mean ± SD, μM): 70 mg BIDx3d EOW, 2.4 ± 0.9; 160 mg QW, 3.5 ± 1.3; 40 mg/d (MTD, 21/28 d), 2.6 ± 2.0. T ½ was approx. 3 hours on all schedules. Conclusions: Pulse dosing of AT-101 appears associated with reduced toxicity than more continuous daily dosing, and may be preferable in combination regimens. No significant financial relationships to disclose.

Abstract Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR. Patients and Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR. Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1–2 diarrhea and acneiform rash being the most common toxicities. Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.

Abstract Abstract 1648 Introduction Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibody therapy. In an attempt to reverse bone marrow infiltration with B-cells and, hence, optimize the biodistribution and tumor dosimetry of 90Y-ibritumomab tiuxetan, we conducted a multicenter, dose escalation, open label study to determine maximum tolerated dose (MTD), safety, and efficacy of a single course of 90Y-ibritumomab tiuxetan after four weekly doses of rituximab in relapsed or refractory low-grade or follicular or transformed CD20+ B-cell NHL. Methods A course of therapy included an initial dose of rituximab 250 mg/m2 plus 5 mCi of 111In- ibritumomab tiuxetan followed by three weekly doses of rituximab at 375 mg/m2 followed two weeks later by rituximab 250 mg/m2 plus 5 mCi of 111In-ibritumomab tiuxetan. Gamma camera imaging for dose estimates was conducted on days 1 and 36 following infusion of 111In- ibritumomab tiuxetan. If dose estimates were in the safe defined limits, and bone marrow on day 29 had less than 25% involvement by NHL, patients received on day 43 250 mg/m2 of rituximab plus a dose of 90Y-ibritumomab tiuxetan. Patients were scheduled to receive 90Y- ibritumomab tiuxetan in one of the dose escalation cohorts (0.4, 0.5, 0.6, 0.7 mCi/kg). Eligible patients were required to have histologically confirmed, relapsed or refractory low-grade or follicular or transformed B-cell NHL with demonstrable monoclonal CD20+ B-cell population in the lymph nodes or bone marrow. Patients with impaired bone marrow reserve, as indicated by prior myeloablative therapies with stem cell rescue, hypocellular marrow, history of failed stem cell collection or external beam radiation therapy to >25% of active bone marrow, and marked reduction in bone marrow precursors of one or more cell lines, were excluded. Results Cohort 1 (0.4 mCi/kg) enrolled 5 patients. Dose escalation was held after significant hematologic toxicity was observed in those patients (1 patient developed grade 4 and 3 grade 3 reversible thrombocytopenia, 4 patients developed grade 4 reversible leukopenia and neutropenia, and 1 patient developed grade 4 febrile neutropenia). One patient in this cohort did not receive the study drug due to the toxicity observed in the previous patients. The protocol was amended and 6 patients were enrolled at a lower dose cohort (0.3 mCi/kg); 1 patient experienced grade 4 neutropenia, whereas grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 2, 3, and 3 patients respectively. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to enroll 6 additional patients. In the expansion cohort, Grade 4 leukopenia and neutropenia were seen in 1 and 2 patients respectively; also, grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 3, 4, and 4 patients, respectively. All hematologic toxicities were reversible and no non-hematologic toxicities were seen with the exception of grade 1 fatigue in 2 patients. Among those who developed hematologic toxicities, the median duration of at least grade 3 leukopenia, neutropenia, and thrombocytopenia were 12 (range, 7–37), 10 (7–30), and 12 (3–44) days, respectively. Six patients had bone marrow involvement by NHL at registration ranging from <5% to 20%. Following 4 weekly doses of rituximab, marrow involvement decreased in all patients with complete clearance in 3 of them. In an intention-to-treat analysis, complete remission, partial remission, stable and progressive disease was achieved in 6 (35%), 8 (47%), 2 (12%), and 1(6%) patients, respectively (fig 1). With a median follow up of 31.7 months (range, 4.3 – 92.6 months), the median progression free survival (fig 2) and time to next treatment (fig 3) were 12.3 and 10.9 months, respectively. The median overall survival has not been reached. Conclusion The MTD of 90Y-ibritumomab tiuxetan administered to patients who have NHL marrow infiltration <25% following 4 weekly doses of rituximab was 0.4 mCi/kg. A 4 weekly course of rituximab decreased NHL marrow infiltration in all patients with marrow involvement and led to complete clearance in 50% of them. Although this regimen was associated with a high response rate, the hematologic toxicity was significant. Disclosures: No relevant conflicts of interest to declare.

Abstract ctDNA analysis offers a non-invasive approach for monitoring response and resistance to treatment. Serial ctDNA testing during neoadjuvant therapy (NAT) may provide early indicators of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesize that (1) assessment of ctDNA levels early in treatment will improve the performance of molecular and imaging-based predictors of pathologic complete response (pCR) to NAT; and (2) levels of ctDNA after NAT are associated with residual cancer burden and recurrence [distant recurrence free survival (DRFS)]. Methods: ctDNA analysis was performed in 84 high-risk stage II and III breast cancer patients randomized to neoadjuvant investigational agent (n=52), AKT inhibitor MK-2206 (M) in combination with paclitaxel (T) followed by doxorubicin and cyclophosphamide (AC) (M+T-&gt;AC), or standard-of-care (T-&gt;AC) (n=32). HER2+ patients also received trastuzumab (H). Serial plasma was collected before NAT (T0), early treatment (3 weeks, T1), between regimens (12 weeks, T2), and after NAT prior to surgery (T3). Mutational profiles derived from pretreatment tumor biopsy and normal matched DNA whole exome sequencing were used to design personalized assays targeting 16 patient-specific somatic variants to detect ctDNA in serial plasma. Results: Of the 84 patients in this study, 43% were HR-/HER2- (TNBC), 35% HR+/HER2-, and 23% HER2+. In total, 74% (61 of 83), 35% (28 of 79), 14% (9 of 65), and 8% (5 of 61) were positive for ctDNA at timepoints T0, T1, T2, and T3, respectively. At T0, ctDNA positivity and levels (average number of mutant molecules detected per mL) were significantly associated with increased tumor burden (by clinical and MRI examination), more aggressive tumor biology (as reflected in higher Mammaprint scores and grade) and subtype (HER2+ and TNBC). Twenty-seven percent (27%) of the 84 patients achieved a pCR and all patients who were ctDNA-positive at T3 (n=5) did not achieve a pCR. Currently, data are being collected to: (1) assess the relationship of ctDNA and MRI imaging in predicting tumor response to therapy; (2) examine the relationship of ctDNA levels before and after NAT with 3-year DRFS and event-free survival (EFS). The results of these analyses will be presented at the SABCS 2018 meeting. Conclusions: Our study provides a platform to evaluate the clinical significance of ctDNA for serial monitoring of response to NAT. Accurate and early response prediction by highly sensitive ctDNA analysis can facilitate a timely and judicious change in treatment to improve patients' chances of achieving a pCR. Finally, personalized ctDNA testing may complement imaging and pathologic evaluation of tumor response to fine-tune pCR as a surrogate endpoint for improved DRFS and EFS. Citation Format: Magbanua MJM, Brown-Swigart L, Hirst GL, Yau C, Wolf D, Ma AA, Bergin E, Venters S, Sethi H, Wu H-T, Salari R, Tin T, Sawyer S, Louie M, Zimmermann B, Lin C-HJ, Keats J, Liang WS, Cuyugan L, Enriquez D, Tripathy D, Chien AJ, Forero A, DeMichele A, Liu M, Delson AL, Asare S, Esserman L, van't Veer L, I-SPY 2 Consortium. Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-01.

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC &gt;6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which disrupts microtubulin and induces apoptosis. Methods This ongoing, phase 1 study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC are eligible. Pts with ≥ Grade 2 neuropathy are excluded. Response is assessed per RECIST v1.1; pts with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts. Tumor biopsies are evaluated for LIV-1 expression. Results To date, 69 pts (18 HR+/HER2–, 51 TN) have received a median of 3 cycles (range, 1–12) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 56 yrs. Pts had a median of 3 prior cytotoxic regimens for LA/MBC; 58 had visceral disease and 37 had bone metastases. No dose-limiting toxicities (DLTs) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Expansion cohorts of TN pts were opened at 2.0 and 2.5 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥25% of pts were fatigue (59%), nausea (51%), peripheral neuropathy (44%), alopecia (36%), decreased appetite (33%), constipation (30%), abdominal pain, diarrhea, and neutropenia (25% each). Most AEs were Grade 1/2; AEs ≥ Grade 3 included neutropenia (25%) and anemia (15%). Febrile neutropenia occurred in 2 pts whose total dose exceeded 200 mg per cycle, including 1 treatment-related death due to sepsis. No other treatment-related deaths occurred on-study. Seven pts discontinued treatment due to AEs. In dose escalation, activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR= CR+PR+SD) of 59% (10 SD), including 1 pt with SD ≥24 wks. Among the 44 EE TN pts (dose escalation plus expansion cohorts), the objective response rate (ORR) was 32% (14 PR) with a confirmed PR rate of 21%, DCR was 64% (14 PR, 14 SD), and clinical benefit rate (CBR=CR+PR+SD ≥24 wks) was 36% (16 pts). For TN pts, median PFS was 11.3 wks (95% CI: 6.1, 17.1); 10 pts remain on treatment. Of 631 MBC tumor samples of all clinical subtypes evaluated for LIV-1, 91% were positive; 75% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy was generally well tolerated and showed encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 32%, confirmed PR rate of 21%, and CBR (≥24 wks) of 36%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort. Citation Format: Modi S, Pusztai L, Forero A, Mita M, Miller KD, Weise A, Krop I, Burris III H, Kalinsky K, Tsai M, Liu MC, Hurvitz SA, Wilks S, Ademuyiwa F, Diab S, Han HS, Kato G, Nanda R, O'Shaughnessy J, Kostic A, Li M, Specht J. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-14.

Abstract Introduction: MutHER is a phase II trial that demonstrated the anti-tumor activity of the pan-HER inhibitor neratinib in HER2mut, non-amplified MBC. The major challenges to accrue to this trial were the large number of pts to screen for the 2-3% HER2mut population and the high rate (24%) of poor quality tumor DNA for sequencing. The goals of this ctDNA study were: 1) the concordance of HER2mut detected by ctDNA versus tumor testing; 2) the incidence of ctDNA HER2mut in HER2 non-amplified MBC; 3) changes in HER2mut variant allele frequency (VAF) on neratinib therapy. Methods: A sample size of 30 negative (neg) controls was needed to ensure 90% confidence if ctDNA testing has &gt;90% specificity in detecting HER2mut. Thus, plasma from MBC pts obtained at screening for MutHER trial (Neg control: 40 pts without HER2mut on tumor testing; Positive (pos) control: 14 pts with known HER2mut who received neratinib) were subjected to Guardant360 ctDNA 70-gene panel sequencing (all exons of HER2 included). ctDNA from the 14 neratinib treated pts were also analyzed at week (wk) 4 and upon progression. ctDNA data from MBC pts clinically tested at Guardant Health were interrogated for HER2mut incidence. Results: Among the 14 pts with tumor pos for HER2mut, ctDNA sequencing identified the same HER2mut in 11, discrepant HER2mut in 1, and neg in 2. The 2 pts with ctDNA neg for HER2mut had progressive disease (PD) and stable disease (SD &gt; 6 months) on neratinib, respectively. Among the 40 neg controls, 8 were not evaluable (no detectable ctDNA or assay unsuccessful) and all 32 successfully sequenced cases were neg for HER2mut. The sensitivity and specificity of ctDNA for HER2mut detection was 11/14 (79%, 90% CI: 53-94%) and 32/32 (100%, 90% CI: 91-100%), respectively. Among the 11 paired baseline and wk 4 samples, 9 (82%) had lower HER2mut VAFs at wk 4 than at baseline, with 1 complete response (CR), 1 partial response (PR), 5 SD, and 4 PD at wk 8 as best tumor response. Two pts had higher wk 4 ctDNA HER2mut VAFs and both had radiographic PD at wk 8. The absolute HER2mut VAF levels at wk 4 were significantly associated with TTP (Spearman rho=-0.69, p=0.02) and tumor size change (rho=0.67, p=0.05). The HER2mut VAFs were significantly higher at progression than wk 4 in all pts (p&lt;0.01). One pt acquired a new HER2mut T798I, which is analogous to the gate-keeper mutation EGFR T790M. The incidence of HER2mut without amplification in unselected consecutive MBC clinically tested by Guardant360 was 3% (48/1,584), with mutation pattern similar to published tumor testing data. Conclusions: ctDNA sequencing is sensitive and highly specific in detecting HER2mut, offering a non-invasive method to identify pts for trials of HER2mut-targeted therapy. Decreased HER2mut VAFs at wk 4 was observed in 82% of cases, consistent with the on-target effect of neratinib. Increased HER2mut VAFs at wk 4 is a potential early marker of progression. Citation Format: Cynthia Ma, Ron Bose, Feng Gao, Rachel Freedman, Melinda Telli, Gretchen Kimmick, Eric Winer, Michael Naughton, Matthew Goetz, Christy Russell, Debu Tripathy, Melody Cobleigh, Andres Forero, Timothy Pluard, Carey Anders, Shana Thomas, Jill Anderson, Caroline Bumb, Kimberly Banks, Richard Lanman, Richard Bryce, Alshad Lalani, John Pfeifer, Daniel Hays, Mark Pegram, Kimberly Blackwell, Philippe Bedard, Hussam Al-Kateb, Matthew Ellis. Circulating tumor DNA (ctDNA) sequencing for HER2 mutation (HER2mut) screening and response monitoring to neratinib in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT011. doi:10.1158/1538-7445.AM2017-CT011