Therapy In Metastatic Setting Research Articles

Nonoperative Management of dMMR/MSI-H Colorectal Cancer following Neoadjuvant Immunotherapy: A Narrative Review.

Immunotherapy with PD-1 blockade has achieved a great success in colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR), and has become the first-line therapy in metastatic setting. Studies of neoadjuvant immunotherapy also report exciting results, showing high rates of clinical complete response (cCR) and pathological complete response. The high efficacy and long duration of response of immunotherapy has prompt attempts to adopt watch-and-wait strategy for patients achieving cCR following the treatment. Thankfully, the watch-and-wait approach has been proposed for nearly 20 years for patients undergoing chemoradiotherapy and has gained ground among patients as well as clinicians. In this narrative review, we combed through the available information on immunotherapy for CRC and on the watch-and-wait strategy in chemoradiotherapy, and looked forward to a future where neoadjuvant immunotherapy as a curative therapy would play a big part in the treatment of MSI-H/dMMR CRC.

Primary CRC tumour location (right-sided versus left-sided) drives differential response to anti-EGFR therapy in metastatic setting

Primary CRC tumour location (right-sided versus left-sided) drives differential response to anti-EGFR therapy in metastatic setting

Abstract P1-19-03: Phase II trial of durvalumab and tremelimumab in the hormone receptor-positive metastatic breast cancer with high tumor mutational burden selected by whole exome sequencing: Korean cancer study group trial (KCSG BR17-04)

Abstract Background: Hormone-receptor (HR) positive breast cancer is the main subtype of breast cancer. Although overall survival of HR-positive metastatic breast cancer (MBC) patients has improved by various therapies including endocrine therapies, CDK4/6 inhibitors, and cytotoxic chemotherapy, it is still considered incurable. Immune checkpoint inhibitors have rarely been clinically tested in HR-positive breast cancer, despite proving anti-cancer activity in early and metastatic triple-negative breast cancer in various trials. We evaluated efficacy and safety of combined durvalumab and tremelimumab in the HR-positive MBC, which was enriched with high tumor mutational burden (TMB). Methods: HR-positive MBC patients who received prior 1 or more lines of therapy in metastatic setting were prescreened with whole exome sequencing (WES) using metastatic or recurred tumor biopsies. Criterion of high TMB was defined as upper 30%. In the beginning, the criterion of high TMB was 2.1 mutations per Mb, based on the retrospective WES database in Yonsei Cancer Center and this criterion was recalculated every 30 cases. Patients who met upper 30% of TMB were treated with combined durvalumab (1500mg every 4 weeks upto 13 doses) and tremelimumab (75mg every 4 weeks upto 4 doses). Response was evaluated every 2 cycles using RECIST 1.1 and toxicity was evaluated using NCI-CTCAE 4.03. Tumor-infiltrating lymphocyte (TIL) and PD-L1 expression were also analyzed to investigate a correlation with TMB. Results: Biopsies of recurrent or metastatic tumors were taken from a total of 119 patients for WES assay. A median turn-around-time of TMB data was 30.0 days (range, 16~67). Of these 119 patients, a median number of nonsynonymous mutations was 2.0 per Mb (range, 0~21.7) with upper 30% criterion of 3.1. High TMB showed a trend toward old age (P=0.074) and single positivity of estrogen receptor (ER) or progesterone receptor (PR) compared to positivity of both ER and PR (P=0.055). TMB was positively correlated with TILs (r=0.289, P=0.005). Thirty patients with high TMB received study treatment with a median 2 cycles (range, 1~13). A median prior lines of therapies in metastatic setting was 4 (range, 1~9). The objective response and clinical benefit rates were 6.3% (2 PRs of 30) and 20% (2 PRs plus 4 SDs of 30). There was one treatment-related mortality due to pneumonitis. Immune-related adverse events included endocrinopathy (n=3; hypothyroidism in 2, hyperthyroidism in 1), enteritis (n=2), skin rash (n=2), pneumonitis (n=1), and so on. Biomarker analyses are underway. Conclusions: WES-based TMB using metastatic tumor biopsy was a feasible platform to prescreen HR-positive MBC patients. Combined durvalumab and tremelimumab showed a modest activity and good tolerability in heavily treated, HR-positive MBC with high TMB. Citation Format: Yong Wha Moon, Eunyoung Kim, Min Hwan Kim, Gun Min Kim, Seul-Gi Kim, YeeSoo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Tae Hoen Kim, Sewha Kim, Yohan Yang, Sangwoo Kim, Joohyuk Sohn. Phase II trial of durvalumab and tremelimumab in the hormone receptor-positive metastatic breast cancer with high tumor mutational burden selected by whole exome sequencing: Korean cancer study group trial (KCSG BR17-04) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-03.

Surgical Treatment of Liver Metastases from Gastrointestinal Stromal Tumor

Introduction: Gastrointestinal stromal tumors (GISTs) are rare tumors which can arise within in most parts of gastrointestinal tract. Most common sites of metastatic spread are liver and the peritoneum. Thyrosinkinase inhibitors greatly improved prognosis of the locally advanced and metastatic disease allowing patients to gain several years of overall survival, yet majority of them will eventually develop progression and succumb to disease. The role of surgical therapy in metastatic setting still remains unclear. Methods: Within the years 2011 - 2020, we performed 29 surgical procedures on 24 patients with liver metastasis from GISTs. We monitored postoperative morbidity, DFI and overall survival in all patients. Results: We identified 24 patients (range 32-80 years), 17 men and 7 women. In 15 patients a metachronous occurrence of metastases was found, most often within the median 2 years after the primary resection (range 2 - 9 years). 9 patients had synchronous disease. 6 synchronous resections were performed (primary tumor and liver), 3 stage resection were performed. 6 large resections were performed, otherwise mainly extraanatomical resections, eventualy combined with RFA (4x) were performed. Only RFA was performed 5 times. The morbidity according to Clavien – Dindo cassification > 2 was 24 %. 20 patients (83%) received systemic treatment before the surgery, and 21 patients (88%) after the surgery. The 1-, 3- and 5-year survival rate was 91%, 86%, and 72%. Conclusion: Surgical treatment of liver metastases from GIST is a safe method. RO resection and a good therapeutic response to systemic thyrosinkinase inhibitors therapy is an important predictive factor of reccurrence. A multidisciplinary approach for treatment of liver metastases from GISTs is necessary. We need further studies to determine the benefits of surgical treatment.

Abstract P5-11-11: Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari study

Abstract Background: There are now many treatment options for estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, there are few reports indicating the optimal treatment sequence for this disease. Information to predict response to treatment is vital for personalized therapy and determining the most beneficial approach for individual patients. In this study, we attempted to determine predictive factors of response to hormonal therapy and survival outcomes using the large-scale databases constructed in the Safari study (UMIN000015168), a retrospective, multicenter cohort study involving 1,072 Japanese patients receiving fulvestrant 500mg for ER+ ABC. We examined the association between clinicopathological factors and time to failure (TTF) of fulvestrant in Japanese ABC patients. Methods: Among 1072 patients, 247 patients were selected for this study. Inclusion criteria was as follows: 1) patients treated with either SERM or AI in the adjuvant setting (AS) with known starting and finishing date of the treatment (patients relapsed on adjuvant treatment were excluded), 2) patients treated with SERM, AI and SERD in the metastatic setting (MS) as the first and the second line treatment. Influence of the adjuvant hormonal therapy on the TTF of the first line and the second line treatment and overall survival (OS) was assessed. Cox proportional hazards model was used for this analysis. Results: Patients treated with SERM in AS had significantly longer TTF of 1st line and 1st+2nd line of hormonal therapy in MS (1st line: HR 1.519, 95% CI 1.04-2.218, p=0.0307, 1st+2nd line: HR 2.372, 95% CI 1.584-3.551, p<0.001) compared with patients treated with AI in AS. Same trend was observed in OS. SERM treated patients in AS had significantly longer OS (OS: HR 2.748, 95% CI 1.574-4.796, p=0.0004) compared with AI treated patients in AS. Since these results described above are the results analyzed by multivariate analysis, they are all statistically significant independent of other factors such as disease free interval in this cohort. Conclusions: Interestingly, once AI-treated patients in AS have relapsed, their hormone sensitivity is lower and survival outcomes are worse compared with SERM-treated patients in AS in this cohort. Our results have consistency with the results of ABCSG-12 trial showing a pronounced higher risk of death for anastrozole-treated patients (Annals of Oncology 26: 313–320, 2015). Since it is a cohort of selected patients who were successfully treated with fulvestrant, prospective analysis would be therefore warranted. Citation Format: Takahiro Nakayama, Hidetoshi Kawaguchi, Norikazu Masuda, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-11.

Abstract PD1-05: Atezolizumab in combination with trastuzumab emtansine or with trastuzumab and pertuzumab in patients with HER2-positive breast cancer and atezolizumab with doxorubicin and cyclophosphamide in HER2-negative breast cancer: Safety and biomarker outcomes from a multi-cohort Phase Ib study

Abstract Background: Chemotherapy and HER2-targeted antibodies are standard-of-care (SOC) treatments (tx) for HER2+ breast cancer (BC) in several settings. Atezolizumab (atezo) + chemotherapy improves progression-free survival (PFS) and overall survival (OS) in PD-L1+ advanced triple-negative BC. Due to the potential for effective tumor cell death and anti-tumor immunity, this study investigated the safety and clinical activity of novel atezo-based combination therapy in HER2+ and HER2-negative BC. In addition, the study evaluated changes in the tumor microenvironment with the combination of immune checkpoint inhibition (atezo) with antibody-dependent cellular cytotoxicity (ADCC) agents (trastuzumab [T] + pertuzumab [P]) or with antibody drug conjugates (ADCs; trastuzumab emtansine [T-DM1]). Methods: GO29831 (NCT02605915) is a multi-cohort Phase Ib study evaluating the safety of atezo-containing tx combinations in patients (pts) with BC. Evaluation of clinical activity and biomarkers were exploratory objectives. PD-L1 status by VENTANA SP142 IHC assay, CD8 IHC and RNA-based gene expression signatures were assessed in pre-tx and on-tx biopsies. See table for patient populations and interventions. Results: At clinical data cutoff (Dec 17, 2018), 76 pts were safety evaluable across 8 tx cohorts. Patient demographics in this completely enrolled study were heterogeneous between cohorts (e.g., hormone receptor status, no. of prior therapies in metastatic setting). No new safety signals were observed beyond the established safety profiles of the individual drugs. Two up-front cycles of atezo combination therapy with anti-HER2 therapy had no detrimental effect on the pathologic complete response (pCR) rates expected with SOC regimens. Increases in PD-L1-expressing tumor-infiltrating immune cells were observed in both HER2+ early BC (eBC) and metastatic BC (mBC) with the combination of atezo + T-DM1 or atezo + T + P. Consistent increases in CD8+ T cells in the tumor area were observed only in eBC. Increases in RNA gene signatures associated with antigen presentation, cytolytic activity and immune checkpoints were observed with both atezo + T-DM1 and atezo + T + P in eBC, whereas statistically significant increases in B-cell (P = 0.0322) and T-cell gene signatures (P = 0.0049) were observed only with atezo + T + P. Conclusions: These tx combinations were tolerable, and safety signals were in line with the known safety profiles of the individual drugs. Biomarker analyses showed that combining atezo with ADCC or ADC agents promoted the activation of the adaptive immune system in the tumor microenvironment. TableCohortPatient PopulationInterventionNo. of Pts1APts with HER2+ mBC or LABCAtezo 1200 mg, T 6 mg/kg, P 420 mg q3w61BPts with HER2+ mBC or LABCAtezo 1200 mg, T-DM1 3.6 mg/kg q3w61EPts with HER2-negative mBC or LABCAtezo 840 mg, doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 and pegfilgrastim or G-CSF q2w for 4 cycles, followed by atezo 1200 mg q3w31FPts with HER2+ mBCAtezo 1200 mg, T 8-mg/kg loading dose (maintenance: 6 mg/kg), P 840-mg loading dose (maintenance: 420 mg) and docetaxel 75 mg/m2 q3w62APts with HER2+ operable LABC or inflammatory eBC (tumor > 2 cm)Neoadjuvant atezo 1200 mg + T 8 mg/kg (c2: 6 mg/kg) + P 840 mg (c2: 420 mg) for 2 cycles, followed by 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 6 mg/mL x min, T 6 mg/kg, P 420 mg q3w prior to breast surgery202BPts with HER2+ operable LABC or inflammatory eBC (tumor > 2 cm)Neoadjuvant atezo 1200 mg + T-DM1 3.6 mg/kg q3w for 2 cycles, followed by 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 6 mg/mL x min, T 6 mg/kg, P 420 mg q3w prior to breast surgery202CPts with HER2+ mBC or LABC with PD on mBC tx or ≤ 6 mo of adjuvant txAtezo 1200 mg, T-DM1 3.6 mg/kg q3w142DPts with HER2+ mBC or LABC with PD on T- and P-containing regimen ≤ 12 wkAtezo 1200 mg, T 8-mg/kg loading dose (maintenance: 6 mg/kg), P 840-mg loading dose (maintenance: 420 mg) q3w1AUC, area under the curve; c2, cycle 2; G-CSF, granulocyte colony-stimulating factor; LABC, locally advanced breast cancer; PD, progressive disease; pt, patient; q2w, every 2 weeks; q3w, every 3 weeks. NCT02605915 Citation Format: Erika Paige Hamilton, Virginia Kaklamani, Carla Falkson, Gregory A Vidal, Patrick J Ward, Monika Patre, Stephen Y Chui, Jacob Rotmensch, Kushagra Gupta, Luciana Molinero, Yijin Li, Leisha A Emens. Atezolizumab in combination with trastuzumab emtansine or with trastuzumab and pertuzumab in patients with HER2-positive breast cancer and atezolizumab with doxorubicin and cyclophosphamide in HER2-negative breast cancer: Safety and biomarker outcomes from a multi-cohort Phase Ib study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-05.

Abstract P4-10-07: Tumor ER protein modulation, molecular characterization and monitoring of cfDNA in phase 1 study of LSZ102 and LSZ102 + ribociclib in patients with ER+ MBC

Abstract Background: LSZ102 is an orally bioavailable selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) mediated gene transcription, induces receptor degradation, and blocks ER-dependent cell growth in preclinical models. This first-in-human study of LSZ102 is evaluating LSZ102 as a single agent (SA) and in combination with the CDK4/6 inhibitor ribociclib or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with locally advanced/metastatic ER-positive (ER+) breast cancer (BC). Here, we present the immunohistochemistry (IHC) and circulating tumor DNA (ctDNA) data obtained from a subset of pts treated with either LSZ102 SA or the combination of LSZ102 and ribociclib. Methods: ER IHC was performed with an antirabbit antibody (clone SP1) on FFPE samples collected at baseline and cycle 1 day 15 (C1D15), and the ER value was reported using the H-score method. A Novartis exploratory PanCancer next-generation sequencing ~600 gene panel for cell-free DNA (cfDNA) was used on plasma samples collected from pts treated with SA or the combination at baseline, on treatment (C1D1, C2D1/C3D1, C5D1, CXD1) at radiological assessments and at the end of treatment (EOT). Results: One hundred fifty-three pts with MBC (median number of prior lines of therapy in metastatic setting = 4; range, 0-10) were treated with LSZ102 SA or the combination of LSZ102 and ribociclib (data cutoff, November 30, 2018). ER protein levels, assessed by IHC H-score, are downregulated in about 75% of C1D15 samples in both SA and combination-treated pts. In this cohort of heavily pretreated pts, cfDNA sequencing was performed on approximately 400 samples from 135 pts, and the genomic landscape is described both at baseline and EOT for pts with detectable ctDNA (~77% of pts). At baseline, approximately 40% of pts had mutations in the ESR1 ligand-binding domain (LBD), and approximately 40% of pts had PIK3CA activating mutations. LBD ESR1 mutations were mainly subclonal with several pts harboring multiple mutations at baseline. The frequency of ESR1 Y537S mutation was no higher in EOT samples after LSZ102 treatment compared with baseline. Moreover, the tumor reduction of target lesions > 30% was observed in pts harboring different baseline ESR1 mutations, including Y537S, treated with either SA or the combination. Furthermore, the longitudinal cfDNA analysis showed a consistent reduction of the overall circulating tumor fraction (ctDNA fraction), from baseline for the majority of patients who achieved either partial response or stable disease with either SA or the combination. Conclusions: Consistent with being a SERD, LSZ102 treatment leads to the degradation of ER in tumor biopsies. The addition of ribociclib does not alter LSZ102-induced ER downregulation. The most common genetic alterations found in cfDNA collected from enrolled ER+ MBC patients before the study treatment were ESR1 and PIK3CA mutations. Importantly, the antitumor activity was observed in pts harboring a variety of ESR1 LBD mutations. Furthermore, enrichment of ESR1 Y537S mutations was not observed after LSZ102 treatment. Finally, the on-treatment longitudinal assessment of cfDNA measuring ctDNA fraction and mutation dynamics is maturing as a useful tool for monitoring the treatment efficacy. Citation Format: Komal Jhaveri, Dejan Juric, Sara Cresta, Yoon-Sim Yap, Francois P. Duhoux, Catherine Terret, Rachel Layman, Alejandro Balbin, Qing Sheng, Serena Liao, Adam Crystal, Giuseppe Curigliano. Tumor ER protein modulation, molecular characterization and monitoring of cfDNA in phase 1 study of LSZ102 and LSZ102 + ribociclib in patients with ER+ MBC [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-07.

485P - Growth modulation index (GMI) as a comparative measure of clinical activity of larotrectinib versus prior systemic treatments in adult and pediatric TRK fusion cancer patients

BackgroundRandomized controlled trials are not feasible for rare cancer populations particularly when the investigational drug targets a molecular alteration shared by several tumor types with different natural histories. Innovative approaches that incorporate patients as their own control can be utilized in this setting. Growth Modulation Index (GMI) is the ratio of time to progression (TTP) with nth line of therapy (TTPn) to the most recent prior line of therapy (TTPn-1), and a GMI ≥1.33 has been proposed as a marker of meaningful clinical activity. We report here the GMI for patients (pts) diagnosed with TRK fusion cancer and treated with larotrectinib, a selective TRK inhibitor. MethodsTRK fusion cancer pts enrolled in 3 clinical trials (NCT02122913, NCT02637687, NCT02576431) who have been on treatment for at least 6 months (or discontinued early) and had at least one prior line of systemic therapy in metastatic setting were eligible. GMI was calculated as a ratio of progression-free survival (PFS) with larotrectinib (PFSLaro) to TTP of the prior line of therapy (TTPn-1). PFS was determined by independent review committee (IRC) assessments using RECIST 1.1 criteria. ResultsAs of a July 30, 2018 data cut, 53 pts (42 adults, 11 pediatric) were eligible. Sixteen pts (30.2%) had 2 prior therapies and 24 (45.3%) had ≥3 prior lines of therapy. Thirteen different tumor types were represented with the largest being soft tissue sarcoma (n=12), lung cancer (n=7), thyroid cancer (n=6), and colon cancer (n=6). The median GMI (IRC) was 2.87 (range: 0.01–48.75, Table). Thirty-five (66.0%) pts had a GMI ≥1.33. Five of 18 pts with a GMI <1.33 are still on treatment and non-progressive at the time of analysis.Table485PTableGMI (PFSLarotrectinib/TTPprior_line)IRC-assessed pts N=53Mean (SD)6.00 (9.97)Median (min, max)2.87 (0.01, 48.75)GMI category, n (%) <1 ≥1 1 to 1.33 ≥1.33 ≥215 (28.3) 38 (71.7) 3 (5.7) 35 (66.0) 32 (60.4) ConclusionsTRK fusion cancer patients treated with larotrectinib had a clinically meaningful improvement in PFS compared to TTP on prior treatment as evidenced by a GMI >1.33 in two-thirds of evaluable patients. Clinical trial identificationNCT02122913, NCT02637687, NCT02576431. Editorial acknowledgementEditorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Legal entity responsible for the studyBayer. FundingBayer. DisclosureA. Italiano: Advisory / Consultancy: Bayer, Epizyme, ImmuneDesign, Lilly, Merck, MSD, Novartis, Roche; Research grant / Funding (institution): AstraZeneca, Bayer, Merck, MSD, Pharmamar, Roche. S. Nanda: Full / Part-time employment: Bayer. K. Keating: Full / Part-time employment: Bayer. B.H. Childs: Full / Part-time employment: Bayer. M. Fellous: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca.

Abstract CT048: Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC)

Abstract Background nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), using intraliposomal stabilisation technology to enable high drug load and in-vivo stability. The expansion of Phase I NCT01770353 evaluated nal-IRI in patients (pts) with mBC. Methods This Phase I expansion study enrolled mBC pts (Cohort 1: ER+ and/or PR+ HER2 BC (C-1); Cohort 2: Triple Negative BC (TNBC, C-2); Cohort 3: BC with active Brain Metastasis (C-3)). Key inclusion criteria: ECOG ≤1; adequate organ function; received &amp;gt;1 to ≤5 prior lines of cytotoxic therapy in metastatic setting, except TNBC pts who could have progressed within 12 months of adjuvant therapy. Pts received nal-IRI 50 mg/m2 (Free-base equivalent, FBE) q2w iv infusion, escalating to 70 mg/m2 FBE q2w, if tolerated. Results 30 pts (10 per cohort) were enrolled: 29 received &amp;gt;1 dose nal-IRI 50 mg/m2 FBE (median age 53 yrs, range 29-70 yrs). Median number of cytotoxic therapies prior to study entry was 3. The most frequent treatment emergent adverse events (TEAEs) were gastrointestinal disorders (all cohorts, 100%), primarily diarrhea (C-1, 100% / C-2, 100% / C-3, 70%), nausea (C-1, 80% / C-2, 56% / C-3, 30%), and vomiting (C-1, 60% / C-2, 33% / C-3, 30%). The incidence of neutropenia was low (C-1, 10% / C-2, 0% / C-3, 10%), all grade 1 / 2. Most common grade 3 TEAEs were diarrhea (28%), nausea (17%), fatigue (14%), hypokalemia (10%) and asthenia (10%), with none reported as grade 4. No grade 5 TEAEs were reported. Partial response (per RECIST) was observed in 10 pts for an objective response rate (ORR) of 35% (C-1, 40% / C-2, 33%) / C-3, 30%). Stable disease was observed in 5 pts (17%). Duration of Response (median, months) was C-1, 7.5 (6.4-13.0) / C-2, 5.6 (3.7-7.4) / C-3, 4.1 (0.0-22.2, extracranial: RECIST) / C-3, 1.8 (0.0-1.9, intracranial: mRECIST). Table 1.Study Demographics, Adverse Events, and Best Overall ResponseDemographicsCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=10Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=30Gender, Female, n (%)10 (100%)10 (100%)10 (100%)30 (100%)Age, Years Median (range)56 (49-68)52.5 (37-70)45.5 (29-63)53 (29-70)Race, n (%)WhiteBlack/AfricanOther8 (80%)02 (20%)8 (80%)1 (10%)1 (10%)7 (70%)1 (10%)2 (20%)23(77%)2 (7%)5(16%)Months Since Metastatic diagnosis, Months Median (Range)63.7 (16-87)20.7 (0-34)32.4 (8-55)24.0 (0-87)Number of Prior Cytotoxic Anti-cancer Regimens Median (Range)3.0 (1-6)3.0 (0-5)32.4 (1-6)3.0 (0-6)Safety PopulationCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=9Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=29ExposureTreatment Duration, Weeks Median (range)6.1 (0-78)12.3 (0-49)13.9 (1-105)12.3 (0-105)Adverse EventsAny TEAE10 (100%)9 (100%)10 (100%)29 (100%)Grade 38 (80%)6 (67%)10 (100%)20 (69%)Grade 41 (10%)06 (60%)3 (10%)TEAE Related to nal-IRI10 (100%)8 (89%)10 (100%)28 (97%)Grade &amp;gt; 36 (60%)3 (33%)3 (30%)12 (41%)TEAE Related to nal-IRILeading to Dose Adjustment*7 (70%)3 (33%)4 (40%)14 (48%)SAEs6 (60%)4 (44%)7 (70%)17 (59%)SAE Related to nal-IRI4 (40%)1 (11%)1 (10%)6 (21%)Duration of Objective ResponseRECIST 1.1RECIST 1.1RECIST 1.1mRECISTMonths Median (Range)7.5 (6.4-13.0)5.6 (3.7-7.4)4.1 (0.0-22.2)1.84 (0.0-1.9)Best Overall ResponseRECISTRECISTRECISTmRECISTComplete Response (CR)0000Partial Response (PR)4 (40%)3 (33%)3 (30%)3 (30%)Stable Disease (SD)03 (33%)2 (20%)3 (30%)Progressive Disease (PD)5 (50%)2 (22%)3 (30%)2 (20%)Not Evaluable (NE)1 (10%)1 (11%)2 (20%)2 (20%)Objective Response RateCR+PR(95% CI)4 (40%)12.2 -73.83 (33%)7.5-70.73 (30%)6.7-65.33 (30%)(6.7-65.3)*n=1 patient in Cohort 1 discontinued treatment due to TEAE related to treatment with nal-IRI CI, Confidence Interval; nal-IRI, Irinotecan Liposome Injection; SAE, Serious Adverse Event; TEAE, Treatment Emergent Adverse EventSystemic tumor response was evaluated according to RECIST version 1.1CNS tumor response was evaluated according to mRECIST (Anders C. et al., Breast Cancer Res Treat, 2014: 146(3):557-66) Conclusion nal-IRI monotherapy 50g/m2 FBE Q2W appears well tolerated, and achieved &amp;gt;30% ORR for systemic and CNS disease among heavily pre-treated mBC pts regardless of receptor status. Citation Format: Jasgit Sachdev, Pamela Munster, Donald Northfelt, Hyo S. Han, Cynthia MA, Fiona Maxwell, Tiffany Wang, Bruce Belanger, Bin Zhang, Yan Moore, Carey Anders. Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT048.

Pharmacokinetic (PK) characterization of irinotecan liposome injection in patients (pts) with metastatic breast cancer (mBC).

e12003 Background: Irinotecan liposome injection (nal-IRI) uses intraliposomal stabilisation technology to enable high drug load and in-vivo stability. This analysis characterizes the PK profile of nal-IRI in pts with mBC. Methods: The expansion of NCT01770353 enrolled 30 pts with mBC over three cohorts (Cohort 1: ER+ and/or PR+ BC [C-1]; Cohort 2: Triple Negative BC [C-2]; and Cohort 3: BC with active Brain Metastasis [C-3]). Key inclusion criteria: ECOG ≤1; adequate organ function; and &gt;1 and ≤5 prior lines of cytotoxic therapy in metastatic setting. Most pts received nal-IRI 60 mg/m2 salt-based equivalent (50 mg/m2 free base equivalent [FBE]) or 80 mg/m2 (70 mg/m2 FBE) q2w by iv infusion, based on tolerance; 2 pts were treated at 40 mg/m2 (35 mg/m2 FBE). Plasma samples were collected over 360h across cycles 1, 2 &amp;3, and analysed using LC-MS/MS for total irinotecan. Data were analysed by a non-compartmental approach using Phoenix Winnonlin, and were compared with values from studies in other tumor types. Results: 21 patients were evaluable for PK analysis (C-1, n=6; C-2, n=7; and C-3, n=8). No trend for accumulation was observed in cycle 2 or 3, when comparing total irinotecan Cmax &amp; exposure (area under the curve at 168 h [AUC168]) versus cycle 1. At 40-80 mg/m2 (35-70 mg/m2 FBE), Cmax of irinotecan tended to increase proportionally with total dose, and was comparable to studies in other tumour types (see Table). Among 29 pts who received nal-IRI, partial response (per RECIST) was observed in 10 pts. The most related TEAEs (≥ 25%) were diarrhea, nausea, vomiting, hypokalaemia, decreased appetite and fatigue. Stable disease was observed in 5 pts. Conclusions: PK parameters in patients with mBC were comparable to historical studies in patients with other tumour types. The safety profile of nal-IRI monotherapy appeared consistent with gastrointestinal and blood disorders. [Table: see text]

Abstract OT1-05-02: A phase II clinical trial of the combination of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor positive triple negative breast cancer

Abstract Background: Androgen receptor (AR) targeted therapy and immunotherapy represent one of the most promising strategies for metastatic triple negative breast cancer (mTNBC), which accounts for 15-20% of all breast cancers. As a nonsteroidal selective androgen receptor modulator (SARM), GTx-024 demonstrated preclinical activity in AR+ TNBC PDX model. Pembrolizumab is a highly selective humanized monoclonal antibody of the programmed cell death 1 receptor (PD-1). The complementary modes of action and low potential for overlapping toxicity make the combination promising in patients with AR+ mTNBC. Trial Design: This is an open-label Phase 2 study for AR+ mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Eligibility Criteria: Eligible patients must have AR+ (&amp;gt;10%, 1+ by IHC) TNBC; failed up to 2 lines of therapy in metastatic setting; and have measurable disease per RECIST1.1. Patients are excluded if they have had prior checkpoint inhibitors or AR targeted agents. Patients with current or prior use of testosterone, testosterone-like agents, androgenic compounds, or anti-androgens (including systemic steroids and immunosuppressive medications)are excluded, as well as current or prior history of noninfectious pneumonitis requiring systemic steroid therapy. Specific Aims: The primary objective is to evaluate the safety/tolerability of GTx-024 and pembrolizumab and determine the response rate (CR or PR via RECIST 1.1) in patients with advanced AR+ TNBC. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination. Statistical Design: A Simon's MiniMax two-stage Phase 2 design will be utilized. Based on the previously reported response rate associated with single agent pembrolizumab (19%), we consider a response rate of 19% for the combination as discouraging, and a 39% response rate as encouraging. As a result, we will initially accrue 15 patients (including 6 patients from safety lead-in treated at the tolerable dose). If 2 or fewer patients respond, we will stop accrual for futility. Otherwise, the study will accrue an additional 14 patients for a total of 29 patients. With 29 patients, if only 8 or fewer respond (≤27.6%), the study will be considered discouraging unless secondary evidence of clinical benefit is substantial. With more than 8 patients responding out of the 29 patients, the combination would be considered promising. This design has 85% power to declare a true response rate of 39% as promising (power), and a 10% probability of declaring a true 19% response rate as encouraging (type I error). The probability of early termination if the true response rate is 19% is 44%. Target Accrual: 29 Study Contact: Yuan Yuan MD PhD, City of Hope Comprehensive Cancer Center; Duarte, CA 91030; Email: yuyuan@coh.org Citation Format: Yuan Y, Frankel P, Synold T, Lee P, Yost S, Martinez N, Tang A, Mendez B, Schmolze D, Apple S, Hurria A, Waisman J, Somlo G, Tank N, Sedrak M, Mortimer J. A phase II clinical trial of the combination of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor positive triple negative 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 OT1-05-02.

Abstract P1-14-06: Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016

Abstract Background: SIRT is a globally licensed technique of Radio-Embolization (RE) of hepatic tumors via intra-arterial infusion of β-particle emitting Yttrium-90 (Y-90) radio-labelled microspheres. It increases response rates and hepatic time to progression in metastatic colorectal cancer when used in combination with 5FU/Oxaliplatin (FOLFOX) chemotherapy with acceptable toxicity profile. FOLFOX gives a radio-sensitizing effect and also controls disease outside the liver. Breast cancer liver metastases (BCLM) patients often have extra-hepatic disease and respond to multiple lines of systemic therapy and SIRT is infrequently used. Methods and patients Between 2010 and 2016 we treated 25 BCLM patients with Y-90 SIRT. Receptor status: 20 ER+ve/HER-2 -ve, 3 ER-ve/HER-2 +ve, 2 triple -ve. Eleven patients had liver only disease with 14 also having known extra-hepatic disease. Average number of previous lines of therapy in metastatic setting: chemotherapy = 2.4; endocrine = 1. Sixty-four % patients had prior Capecitabine (n=16); 12% platinum (n=3, all Carboplatin). Twenty patients received chemotherapy with SIRT: 17 had modified FOLFOX6 (Oxaliplatin/bolus 5FU day1, infusional 5FU day 1-3 (46 hrs); 3 patients had Modified de Gramont style 5FU alone. Five patients had no chemotherapy. Sir-spheres were inserted on day 2 of FOLFOX with the 5FU infusion pump continuing to day 3. Further 2-weekly FOLFOX chemo cycles were at clinician's discretion: average number delivered 3.8. Four patients had the liver treated in two halves, approximately 6 weeks apart. One patient received SIRT only to half the liver. Patients were imaged with PET-CT/CT before and 2-3 months after SIRT. Retrospective case note review was performed and data correlated to evaluate tumor response (RR); hepatic and extra hepatic progression free survival (HPFS and EHPFS) and overall survival (OS). Accurate toxicity data was not recorded. Results Hepatic CT response rates: PR 56% (n=14), SD 28% (n=7) and PD 16% (n=4). Hepatic PET response rates: CR 32% (n=8), PR 40% (n=10), SD 12% (n=3), PD 16%(n=4). (Overall PET liver disease control rate = 84%). Eight patients (32%) had extra-hepatic PD at first assessment. Of them, 4 had PR, 2 SD and 2 PD in the liver at that assessment. Two HER-2 +ve patients had brain metastases as first sign of PD within 75 days, an area not previously screened. Of 16 pre-treated with Capecitabine, liver CT response rates: 62.5% PR, 18.75% SD (n=10,3). Post SIRT/FOLFOX, average number of therapy lines: 2 for chemo and 0.75 for endocrine, with 8 patients still alive at time of censoring. Median OS: 766 HPFS: 210 days (CI 140-286). Median EHPFS in patients with extra-hepatic disease: 152 days (CI 96-636). Conclusions SIRT with FOLFOX in previously treated BCLM patients produces high response rates, excellent tumor control and time to progression in the liver with good overall survival. It does not seem to decrease the ability to give further lines of chemotherapy and can be considered as an option for breast cancer patients with liver metastases. Citation Format: Wilson G, Mullamitha S, Bentley D, Bell J, Mullan D, Carter L, Chittalia A, Howell S, Laasch H-U, Westwood T, Jeans S, Tipping J, Ryder D, Farquharson F, Arumugam P, Sheen A, Rajashanker B, Armstrong A, Misra V, Manoharan P, Lawrance J. Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016 [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 P1-14-06.

P-275 - The choice of irinotecan or oxaliplatin-based chemotherapy in metastatic colo-rectal cancer as first line treatment: Impact on survival (ERCC1 and TOPO1 adjusted analysis)

Introduction: The choice between Irinotecan and Oxaliplatin-based chemotherapy as first-line treatment in metastatic colo-rectal patients is a difficult task. No specific criteria, guidelines or recommendation were defined. The oncologist should take into account some important demographic, clinical, biological and molecular variables: ERRC1, TOPO1 expression, all-RAS and/or B-RAF mutations, tumor location, MMR, CIMP status, etc. Methods: The primary endpoint of this retrospective and exploratory analysis was survival, defined as time-to-event variable, from primary diagnosis to death or date of last visit (for censored patients). The impact of chemotherapy (Irinotecan or Oxaliplatin-based) was analysed using multivariate Cox regression analysis. A crude (unadjusted) univariate analysis was performed as first-step. Covariates as age, gender, tumor location (colon vs rectal), type of molecular (targeted) treatment (Bevacizumab vs Cetuximab vs none), ERCC1 and TOPO1 expression (as defined by immunohistochemistry: the product (H-score) between the percentage of positive cells (0 to 100%) and intensity of expression (o to 3)). Hazard ratios were calculated (including 95% confidence interval) for unadjusted univariate analyses (Irinotecan vs Oxaliplatin-based chemotherapy) and for multivariate analyses having as covariate: a).ERCC1; b).TOPO1; c).ERCC1 + TOPO1; d).ERCC1 + TOPO1 + age + tumor location + gender + molecular treatment. No correction for multiplicity of tests was performed. Results: The cohort of interest was represented by 65 patients with metastatic colorectal cancer, treated between May 2011 - March 2017 in Saint-Constantin Hospital, Medical Oncology Department (Brasov, Romania). Gender distribution: 60% males and 40% women; tumor location: 77% colon and 23% rectal cancer. Chemotherapy regimens were Irinotecan (78%) and Oxaliplatin-based (22%). Median age was 60 years (range 37-81). Forty percent of patients were treated with Bevacizumab, 32% with Cetuximab and 28% by chemotherapy only. Median H-scores were 200 (ERCC1) and 190 (TOPO1). It seems that ERCC1 expression is generally bad (higher H-scores), compared with TOPO1 expression. At 71 months from the initial diagnosis, 53% of patients were still alive (95% CI, 21-85%). Hazard ratio for unadjusted univariate analysis (Irinotecan vs Oxaliplatin-based chemotherapy: HR = 1,81 (95% CI, 0,58-5,61), p-value=0,31) and for multivariate analysis having as covariate: a).TOPO1, HR = 1,99 (95% CI, 0,60-6,60), p-value=0,26; b).ERCC1, HR = 2,39 (95% CI, 0,73-7,80), p-value=0,15; c).ERCC1 + TOPO1, HR = 2,42 (95% CI, 0,70-8,33), p-value=0,16; d).ERCC1 + TOPO1 + age + tumor location + gender + molecular treatment, HR = 2,59 (95% CI, 0,67-9,97%), p-value=0,17 (as represented in Figure). ERCC1 had a powerful impact on survival (p-value=0,03), only. The risk of death for rectal cancer patients is 51% lower compared with colon cancer patients, no matter the type of chemotherapy and molecular treatment. Updated data will be presented at the end of June 2017. Conclusion: The probability of death is two and a half times lower in patients treated with Irinotecan-based regimens (FOLFIRI) compared to those treated with oxaliplatin (FOLFOX), as first-line therapy in metastatic setting. Hazard ratios were all (including 95% CI) above the “no effect” axis. Despite the low number of patients and a low statistical power, results clearly demonstrated the statistically significant predictive role of ERCC1 expression on survival in a multivariate Cox regression analysis. As showed, taking into account the ERCC and TOPO1 expression, FOLFIRI + molecular treatment should be the preferred regimen in first-line setting.

Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.

1026 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3Kα isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that failed standard therapy. Methods: In this phase I study, pts received alpelisib daily (cohort 1: 300 mg, (-1): 250 mg) and T-DM1 3.6 mg/m2 on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Data cut-off is Jan. 1, 2017. Results: 17 pts were enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (0-13) including 9 pts who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 2 (1-5). Median number of cycles per pt who completed at least 1 cycle was 8 (1-19). Five pts were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 53%), fatigue (n = 9, 53%), nausea (n = 7, 35%), and rash (n = 8, 47%). Grade 3 alpelisib-related AEs included rash (n = 7), hyperglycemia (n = 3), weight loss (n = 1), hypertension (n = 2), and pancreatitis (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Median follow-up was 11.6 months (0.3-19.5). Median PFS was 6 months (95% CI 2.9-10.6). In 11 pts without prior T-DM1 mPFS was 4.3 months (95% CI 2.0-8.8) and in 6 pts with prior T-DM1 it was 10.6 months (95% CI 1.6-12.6), p = 0.18. Conclusions: The combination of alpelisib 250 mg daily and T-DM1 appears to be safe in HER2-positive MBC pts with significant anti-tumor activity, even in pts previously treated with T-DM1. A phase II study is planned. Clinical trial information: NCT02038010.

Abstract OT3-01-06: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background: Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design: A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be an adaptive design with 10 patients, using the time-to-event continual reassessment method. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, approximately 36 pts (range: 32-40) are expected for the P1/2. The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C2D1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy on C2D1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on HER2-directed therapy in metastatic setting, including Pertuzumab and T-DM1 3. Measurable or non-measurable disease 4. LVEF great than 50% 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims: 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods: Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual: Sample Size: 32-40 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Trial accruing since Fall 2014. Citation Format: Kalinsky K, Chi D-C, Lee S, Bhardwaj A, Makower D, Cigler T, Crew KD, Hershman DL, Califano A, Silva J, Maurer M. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-06.

Abstract OT1-1-09: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be an adaptive design with 10 patients, using the time-to-event continual reassessment method. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, approximately 36 pts (range: 32-40) are expected for the P1/2. The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C2D1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy on C2D1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on &amp;gt;2 HER2-directed therapy in metastatic setting, including Pertuzumab and T-DM1 3. Measurable or non-measurable disease 4. LVEF &amp;gt;50%. 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual Sample Size: 32-40 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Trial will start accruing July 2014. Citation Format: Kevin Kalinsky, Dow-Chung Chi, Shing Lee, Amy Tiersten, Della Makower, Ellen Chuang, Katherine D Crew, Dawn L Hershman, Jose Silva, Andrea Califano, Matthew Maurer. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-09.

Abstract P6-06-32: 4EVER: Does mTOR inhibition have a major clinical impact on bone health in postmenopausal women with hormone receptor positive (HR+) locally advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE)?

Abstract Introduction: BOLERO-2, a multi-national, double-blind, placebo-controlled, phase 3 study in postmenopausal women with HR+, HER2- advanced breast cancer (BC) progressing after non-steroidal aromatase inhibitors (NSAI), showed significant benefit in PFS with the addition of the mTOR inhibitor EVE to EXE compared to EXE alone (Baselga J 2012). The BOLERO-2 bone sub study indicated an influence of EVE on bone health after 6 and 12 weeks of treatment (Gnant M 2012). To further investigate the long term influence of mTOR inhibition on bone health, we initiated the phase IIIb, multi-center, open label study 4EVER for postmenopausal women with HR+ locally advanced or metastatic breast cancer treated with EVE +EXE. The primary endpoint is the overall response rate (ORR) after 6 months. Secondary endpoints include progression free survival after 6 and 12 months, ORR after 12 months, overall survival, quality of life, health utilities and health care resources. The exploratory objectives focus amongst others on the assessment of biomarkers of bone turnover. Methods: Main inclusion criteria were postmenopausal women with metastatic or locally advanced, ER+, HER2- breast cancer refractory to NSAI. Markers of bone turnover (P-I-NP, CTX, OPG, RANKL, vitamin D, FSH and estradiol) are being assessed at baseline and after 4, 12 and 24 weeks on treatment. Results: Baseline characteristics: 334 postmenopausal patients were screened and 297 were enrolled in 5 months. The hormone receptor assessment was performed in 71.0% from primary tumor and in 29% from the metastases (ER+/PgR+ 77.5%, ER+/PgR- 21.5%). The mean time since initial diagnosis was 9.2 years. Mean time since first recurrence/ metastasis was 48.1 months and mean time since most recent recurrence / metastasis 2.4 months. The stage at primary diagnosis was M0 74.2% and M1 22.0%. 68.7% of the patients had bone lesions. Most recent antineoplastic medications were in the adjuvant (24.8%), neoadjuvant (1.1%) and palliative setting (71.0%). 25.6% of the patients had one, 16.4% two and 57.9% three and more prior therapies in metastatic setting. The results of the baseline bone and hormone maker analysis for baseline and after 4, 12 and 24 weeks on treatment will be presented. Conclusion: This exploratory bone study will provide further insights into the influence of mTOR inhibition on bone turnover and overall bone health in women with advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-32.

A phase II study of intratumoral administration of the autologous immature dendritic cell (DC) vaccine used after lesion photodynamic therapy (PhDT) and immunomodulation with cyclophosphamide (Cy) in pretreated patients with disseminated malignant melanoma.

3088 Background: Immature DC can be loaded in vivo with tumor-specific antigens after tissue destruction and induce specific immune response even in pretreated patients with unfavorable prognosis. We assess clinical efficacy of this approach in melanoma patients after at least 1 line of drug therapy in metastatic setting. Methods: Totally, 14 pts were enrolled: 11 men, 3 women. Stage M1a in 4 (28%) pts, M1b in 1 (7%) and M1c was in 9 (64%) pts. Patient received Cy 300 mg IM at D0, photoditasine (PH) at D3, PhDT therapy on injectable lesion 2 hrs after PH (662 nm, 300 J). The immature DC derived from peripheral blood stem-cells were injected in irradiated lesion 6 hrs after photodynamic therapy at D3 and daily until D7 of the 21-day cycle. Vaccine dose was 60-100*10^6 cells. Toxicity was measured by CTC AE v4, efficacy by RECIST 1.0. Primary endpoint was clinical benefit rate (CBR), secondary – overall survival (OS), response rate (RR), time to progression (TTP) and toxicity. Results: 14 pts were evaluable for toxicity, 13 for response. 37 cycles of therapy were performed. 2 patients achieved PR lasting 393 and 218+ days. 5 patients were stable for 33+, 108, 113, 168 and 239 days. RR was 15 (95% CI 2-39)%, CBR – 54 (95% CI 27-81)%. Median OS was 334 days, TTP – 113 days. RR was well correlated with OS (p=0,014). No SAE or AE of 4th degree occurred. The only grade 3 toxicity was fever. All grade 1-2 AEs were immune-related: fever (the most frequent AE), pain in the lesions, flu-like reactions, myalgia as well as high serum ALT, AST and bilirubin in patients with liver metastases. Conclusions: Thus, using the described approach for immunotherapy of melanoma has clinical efficacy and worth further developing.