Site Of First Progression Research Articles

Abstract PO5-20-02: Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET)

Abstract Background: Despite treatment with trastuzumab-based therapy, up to half of patients with HER2+ advanced/metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for advanced HER2+ MBC remains a taxane, trastuzumab, pertuzumab (TP) which demonstrates poor brain permeability. Isolated brain relapse with stable or absent extracranial disease remains a clinical problem in both the adjuvant (Untch et al., ESMO 2019 Congress) and metastatic settings (Noteware et al., Breast Cancer Res Treat. 2023). Current guidelines recommend continuing current systemic therapy in the setting of first isolated brain relapse following local therapy. Tucatinib, a brain-penetrable HER2-targeting tyrosine kinase inhibitor, when added to trastuzumab and capecitabine improves intracranial progression free survival (PFS) and overall survival (OS) in patients with stable or active HER2+ BrMs. We hypothesize that adding tucatinib to TP or T-DM1 in patients with HER2+ MBC with isolated brain relapse or progression could delay or prevent the development of further intracranial lesions and improve OS. Methods: BRIDGET (NCT05323955) is a single arm, phase II, multicenter study of tucatinib added to TP or T-DM1 after local therapy in patients with isolated brain relapse or progression. A total of 48 patients at 9 U.S. sites as part of the Hoosier Cancer Research Network (HCRN) with metastatic HER2+ breast cancer will be enrolled after 1st or 2nd BrM relapse or progression within 8 weeks of local therapy. Patients must currently be receiving standard of care treatment with TP or T-DM1 in the metastatic setting, or adjuvant trastuzumab-based or T-DM1 therapy with isolated brain recurrence. Extracranial disease must be stable per RECISTv1.1 or absent. Patients may not have leptomeningeal disease or untreated brain lesions over 5 mm. Patients will receive continuous tucatinib added to their current therapy (TP or T-DM1). The primary objective is intracranial PFS compared to a historical control (H0: PFS < 5 months (mos), HA: PFS > 8 mos) of the HER2CLIMB clinical trial where patients could continue on trial with isolated brain progression. In these patients, median time from brain progression to second progression or death was 7.6 mos (95% CI, 3.9 to 11.3 mos) in the tucatinib arm versus 3.1 mos (95% CI, 1.2 to 4.1 mos) in the control arm (Lin et al., J Clin Onc 2020). Secondary endpoints include PFS by RECISTv1.1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression (brain versus non-brain), OS, and toxicity in patients with BrM. Collection of correlative specimens including archival tissue, cerebrospinal fluid (optional), whole blood for ctDNA are planned. Patient-reported outcomes surveyed utilizing the FACT-BR and FACIT-Fatigue questionnaires are also included for future analyses. As of 7/06/23, accrual is 5 patients of the anticipated 48 patients overall, across 5 sites (Duke University, Dana Farber Cancer Institute, Ohio State University, Providence Portland Medical Center, and Washington University in St. Louis) currently open. An additional 4 sites are pending opening. Those interested in this trial can reach out to the study Principal Investigators, Carey Anders, MD (carey.anders@duke.edu) or Sarah Sammons, MD (sarahl_sammons@dfci.harvard.edu). Citation Format: Sarah Sammons, Amanda Van Swearingen, Laura Noteware, Nusayba Bagegni, Kelly Moulton, Stevie Threatt, Denise Jaggers, Shannon Shea, Eric Lipp, Erin Riley, Sin-Ho Jung, Gloria Broadwater, Masey Ross, Kimberly Strickland, Sasha Beyer, Alison Conlin, Aki Morikawa, Rashmi Murthy, Carey Anders. Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-02.

TIPS-19 TRIAL IN PROGRESS: SECONDARY BRAIN METASTASES PREVENTION AFTER ISOLATED INTRACRANIAL PROGRESSION ON TRASTUZUMAB/PERTUZUMAB OR T-DM1 IN PATIENTS WITH ADVANCED HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2+ BREAST CANCER WITH THE ADDITION OF TUCATINIB (BRIDGET)

Abstract Despite trastuzumab-based therapy, up to half of patients with HER2+ metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for HER2+ MBC, taxane/trastuzumab/pertuzumab (TP), demonstrates poor brain permeability. Isolated brain relapse with stable/absent extracranial disease remains a clinical problem in both the adjuvant and metastatic settings, and current guidelines recommend continuing current systemic therapy following local therapy. Tucatinib, a brain-penetrable HER2-inhibitor, when added to trastuzumab and capecitabine improves intracranial PFS and OS in patients with stable/active HER2+ BrMs. We hypothesize that adding tucatinib to TP or T-DM1 in patients with HER2+ MBC with isolated brain relapse or progression could delay or prevent the development of further intracranial lesions and improve OS. BRIDGET (NCT05323955) is a single arm, phase II study of tucatinib added to TP or T-DM1 after local therapy in patients with isolated brain relapse or progression. A total of 48 patients at 9 U.S. sites through HCRN with HER2+ MBC will be enrolled after 1st or 2nd BrM relapse/progression within 8 weeks of local therapy. Patients must currently be receiving TP or T-DM1 in the metastatic setting, or adjuvant trastuzumab-based or T-DM1 therapy with isolated brain recurrence. Extracranial disease must be stable per RECISTv1.1 or absent. Patients will receive tucatinib added to their current therapy. The primary objective is intracranial PFS compared to a historical control (H0: historical iPFS <5 months (mos), HA: iPFS >8 mos) of the HER2CLIMB trial. In these patients, median time from brain progression to second progression/death was 7.6 mos with tucatinib versus 3.1 mos in the control arm. Secondary endpoints include PFS by RECISTv1.1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression, OS, and toxicity. Collection of correlative specimens and patient-reported outcomes (FACT-BR, FACIT-Fatigue) are also included.

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases

It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. ClinicalTrials.gov Identifier: NCT02614794.

1st Line Pembrolizumab in Treatment of Stage IV NSCLC Patients – A Pattern of Failure Analysis with Associated Survival Outcomes

<h3>Purpose/Objective(s)</h3> To investigate patterns of failure in metastatic NSCLC patients treated with pembrolizumab and analyze factors associated with oncologic outcomes. By discerning these patterns, a subset of patients could be identified that may benefit from local consolidative therapy. <h3>Materials/Methods</h3> This retrospective analysis included 118 patients diagnosed with metastatic NSCLC from January 2015 to May 2020 at a single institution. Each patient received at least one cycle of pembrolizumab and had radiographic follow up of at least 3 months. Patterns of failure were identified by first radiographic disease progression event after initiation of pembrolizumab. Initial failures were grouped by site of first progression (local (L), regional (R), distant (D), or any synchronous combination of the three (L+/-R+/-D)) as well as pattern of progression (existing lesions only (E), new lesions only (N), or both (B)). Descriptive statistics were used to report patterns of failure. Kaplan-Meier method, log-rank test, and Cox proportional hazard model were used to calculate OS/PFS outcomes, compare subgroups, and analyze patient characteristics for significance. <h3>Results</h3> Median follow up was 8.6 months. The majority of patients presented with synchronous and poly-metastatic (>5 metastases) disease (86% and 70%, respectively). Overall, 71 patients (60%) demonstrated progression. The most common site of first failure was a combination of local, regional, and/or distant progression (51%) and the most common pattern was progression at an existing lesion alone (42%) or at both a new and existing lesion (42%). By anatomical location of first progression, the majority of progression events occurred in existing locoregional lesions: 26 lung events and 24 regional LN (mediastinal/hilar) events. Median time to treatment failure was 4.6 months. Median OS and PFS for the entire cohort were 15.8 and 7.3 months, respectively. Median OS was 41.7 (no progression) vs 12.6 (progression) months (p<0.0001). Stratified by site/pattern of failure, only OS (L: 15.8 mo, R: 21.6 mo, D: 14.3 mo, combination 8.2 mo (p=0.001) and E: 12.6 mo, N: 22.2 mo, B: 8.5 mo (p=0.004)) was statistically significant. Median OS was significantly improved in patients who experienced oligoprogression vs systemic progression (19.4 vs 8.5 mo, p<0.0001). On UVA, only history of prior systemic therapy (OS and PFS) and intracranial disease at initial time of diagnosis (PFS only) were significant. On MVA, age < 65 (OS only), history of prior systemic therapy (OS and PFS), lower N stage (PFS only), and intracranial disease (PFS only) were found to be significant. <h3>Conclusion</h3> As the paradigm for treating metastatic NSCLC patients continues to evolve, elucidating patterns of failure and the factors associated with it can aid in identifying those who would benefit from additional (and potentially aggressive) local therapy. Further investigation is warranted.

121P Treatment of unresectable stage III NSCLC: Real-world study and literature review

The standard treatment of unresectable stage III non-small cell lung cancer (NSCLC) is combined chemoradiotherapy (CRT), delivered either concurrently (cCRT) or sequentially (sCRT). There is, however, limited data on the outcomes and safety of CRT in real-world setting. We performed an analysis of the Leuven Lung Cancer Group (LLCG) experience with CRT for unresectable stage III NSCLC prior to the era of consolidation treatment with immunotherapy. We conducted a retrospective, monocentric cohort study at the university hospital UZ Leuven, Belgium, and retrieved 163 consecutive patients who were treated with CRT for unresectable stage III NSCLC between January 1st 2011 and December 31st 2018. Patient and tumor characteristics, treatment patterns, toxicity, and primary outcome parameters were analyzed. Chemotherapy was given concurrently in 108 patients, sequentially in 55. Overall tolerability was good with two thirds of patients having no severe adverse events: severe febrile neutropenia (9,2%), ³ grade 2 pneumonitis (16%), or ³ grade 3 esophagitis (19%). Adverse events were more frequent in the cCRT than sCRT group. Median PFS was 13.2 months (95% CI 10.3-16.2). In the patients with progressive disease, the site of first progression was locoregional in 36% and distant in 64%, with no significant difference between cCRT and sCRT. Median OS was 23.3 months (95% CI 18.3-28.0), with a 47.5% survival rate at 2 years and 29.4% at 5 years. In multivariate Cox regression analysis, Karnofsky performance status, stage (UICC TNM 8th edition) and COPD were significant factors for OS, while sequence of therapy (cCRT versus sCRT) lost significance in multivariate testing. Our real-world PFS, OS and toxicity results are comparable to those reported in randomized controlled trials (RTOG 0617, PROCLAIM). Sequence of therapy did not independently associate with OS, likely since the choice for a sequential versus concurrent approach is strongly influenced by other main drivers of survival such as performance status. This study provides a clinically relevant real-world benchmark on the outcomes of cCRT and sCRT before the start of the immunotherapy era in this setting.

Assessment of the value of adjuvant radiotherapy for treatment of gastric adenocarcinoma based on pattern of post-surgical progression

PurposeTo assess the value of adjuvant radiotherapy for treatment of gastric adenocarcinoma and to investigate subgroups of patients suitable for adjuvant radiotherapy.Methods and materialsData from 785 patients with gastric adenocarcinoma who had undergone D1/D2 radical resection and adjuvant chemotherapy were collected, the site of first progression was determined, and the relationship between the rate of local recurrence and clinicopathologic features was analyzed.ResultsBy the end of the follow-up period, progression was observed in 405 patients. Local recurrence was observed as the first progression in 161 cases. The local recurrence rate was significantly lower than the non-local progression rate (20.5% vs 31.5%, p=0.007). Multivariate Cox regression analysis showed a significant relationship among degree of differentiation, T stage, N stage, and rate of local recurrence.ConclusionsNot all patients with gastric carcinoma required adjuvant radiotherapy. However, patients with poorly differentiated cancer cells, advanced T stage (T3/T4), and positive lymph nodes, which included patients in the T4N1-2M0 subgroup, were recommended for adjuvant radiotherapy.

Radiotherapy for inferior vena cava tumor thrombus in patients with hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) with inferior vena cava (IVC) involvement is a rare disease with poor prognosis. This study aimed to evaluate the outcome of HCC patients receiving radiotherapy (RT) to IVC tumor thrombus.MethodsA total of 42 consecutive HCC patients treated with RT to IVC tumor thrombus between September 2007 and October 2018 were enrolled. Overall survival (OS), the response of IVC thrombus, prognostic factors and failure pattern were assessed.ResultsThe median follow-up time was 4.4 months. The median RT equivalent dose in 2-Gy fractions was 48.75 Gy (range, 3.25–67.10). The objective response rate of IVC thrombus was 47.6% (95% confidence interval [CI], 33.3–64.3%). The OS rate at 1 year was 30.0%, with a median OS of 6.6 months (95% CI, 3.7–9.5) from the start of RT. On multivariate analysis, Child-Pugh class, lymph node metastasis, lung metastasis and objective response of IVC thrombus were independent predictors for OS. Lung was the most common site of first progression in 14 (33.3%) patients. For 32 patients without lung metastasis before RT, use of systemic treatment concurrent with and/or after RT was associated with a significantly longer lung metastasis-free survival (5.9 vs. 1.5 months, p = 0.0033).ConclusionsRT is effective for IVC tumor thrombus of HCC with acceptable adverse effects. RT might be a treatment option incorporated into combination therapy for HCC involving IVC.

Neoadjuvant therapy does not alter pattern of progression in pancreatic adenocarcinoma

Background: Neoadjuvant therapy (NAT) has been accepted as a strategy to treat borderline resectable and locally-advanced pancreatic adenocarcinoma (PDAC). FOLFIRINOX in addition to radiation therapy allows selected patients the opportunity to undergo a potentially curative operation, with a high rate of margin-negative resection. Given that the vast majority of PDAC patients that undergo curative treatment either recur or develop distant metastases, we sought to evaluate if NAT leads to changes in patterns of progression. Methods: Using the MGH prospectively maintained PDAC database we identified patients with resectable PDAC. First site of progression was designated as either locoregional (LR) or as distant metastasis (DM). DM included metastases to liver, lung, peritoneum, or other sites. If both LR and DM were identified on imaging, patients were categorized as DM. Patients with resectable disease were treated with upfront resection, adjuvant chemotherapy, and individualized radiotherapy. In order to understand if NAT in borderline resectable patients led to a difference in site of first progression compared to resectable disease, we investigated patients from the MGH Phase-II trial evaluating total neoadjuvant therapy (TNT) in borderline-resectable PDAC (Murphy et al. Jama Oncol, 2018), in which site of first progression was collected prospectively. P-value < 0.05 was considered significant. Results: Using the MGH PDAC database from 2011 to 2017, 99 resectable patients progressed during a median follow-up of 60.1 months. The median disease-free survival (mDFS) in this group was 13.0 months. The median overall survival (mOS)was 23.4 months. Patients with resectable PDAC were treated with adjuvant chemotherapy (100%) and radiation (35.5%). Margin-negative resection was achieved in 77 of 99 patients (77.8%). In resectable patients, site of first progression was found to be LR in 18.2% of patients and was DM in 81.8% of patients. We compared resectable patients to patients from the MGH Phase-II trial (NCT01591733) evaluating TNT in borderline resectable PDAC. Out of 48 evaluable patients, 36 recurred during the median follow-up period of 36 months. The mDFS was 17.7 months and the mOS was 37.7 months. All patients in this trial received neoadjuvant chemotherapy with FOLIFIRINOX, followed by chemoradiation. 31 of 48 patients (65%) achieved an R0 resection. Out of these patients, 50% had site of first progression locoregionally and 50% had site of first progression as DM. The distribution of site of first progression was different between the two cohorts (p < 0.0001) and demonstrated an increase in the early failure of locoregional control in patients with borderline resectable PDAC treated with NAT. Conclusion: Upfront resectable patients with PDAC who progress after curative-intent resection and adjuvant therapy do so more often distantly than locoregionally. However, in patients with borderline resectable PDAC treated with neoadjuvant chemotherapy and radiation, there is an increase in local failure as site of first progression, versus distant control in comparison to resectable patients treated with adjuvant therapy. This may be a reflection of altered disease biology between borderline and resectable patients, or better distant control with NAT.

264P - Progression-free survival (PFS) and site of first progression in HER2+ metastatic breast cancer (MBC) patients (pts) with (w) or without (w/o) brain metastases: A pooled analysis of tucatinib phase I studies

264P - Progression-free survival (PFS) and site of first progression in HER2+ metastatic breast cancer (MBC) patients (pts) with (w) or without (w/o) brain metastases: A pooled analysis of tucatinib phase I studies

Retrospective review of concurrent chest radiation and chemotherapy (CRT) in newly diagnosed stage IV non-small cell lung cancer (NSCLC) with oligometastatic disease (OM) treated with stereotactic radiation.

e20539 Background:The primary treatment for patients (pts)with stage IV NSCLC is palliative chemotherapy (CT), with a median OS of approximately 10-12 months, and 5-year survival of ~2%. Several studies have demonstrated that pts with a lung nodule with a solitary brain or adrenal metastasis can achieve relatively high 5-year survival rates with resection of the metastasis and the lung nodule. Studies have also demonstrated that OM can be effectively treated with stereotactic body radiation (SBRT) or stereotactic radiosurgery (SRS) to the brain. We hypothesize that treatment of OM with SBRT and/or SRS and treatment of the thoracic disease with CRT will improve survival over palliative chemotherapy alone. Methods:A retrospective review of charts in the RADTRACS database at the Univ of Florida was conducted between 1/1/2010 - 6/30/2015 to identify pts with newly diagnosed stage IV NSCLC with 5 or less OM at diagnosis that were treated with concurrent CT and definitive RT (60-66 Gy) to the primary lung mass in addition to SRS and/or SBRT to the OM. Date and site of first progression, and date of death/last follow-up were noted. Endpoints included median progression free survival (PFS) and median overall survival (OS). Results:26 pts met these criteria. 20 pts (77%) had recurrence of disease after treatment with CRT + SRS/SBRT. Median PFS was 6 months, and median OS was 14.4 months. Of the 20 recurrences, 10 (50%) were in the brain, while 10 (50%) were in non-CNS sites. One year OS was 60% and 3-year survival was 33% in our patients. When pts with CNS OM at diagnosis were compared to non-CNS OM, PFS (5.5 vs 5.8 months, respectively, p &gt; 0.05) and OS (16.6 vs 13.8 months, respectively, p &gt; 0.05) were similar. 8/12 CNS OM pts progressed in the brain while only 3/9 non-CNS OM progressed in the brain. Of the 5 patients with no progression, 4/5 had non-CNS OM at diagnosis. Conclusions:When compared to standard palliative CT where median OS 10-12 months, median OS was 14.4 months in our pts treated with CRT + SBRT/SRS. This data suggests a possible role for more aggressive treatment of stage IV NSCLC pts with SBRT/SRS to OM and definitive chest CRT.

Abstract P4-21-14: A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP

Abstract P4-21-14: A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP

3:45 PMAbstract No. 8 - SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC)

3:45 PMAbstract No. 8 - SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC)

SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC).

637 Background: SIRFLOX, an international multi-centre open-label RCT in first-line pts with non-resectable, liver-only or liver-dominant mCRC, showed that compared to FOLFOX (± bev) chemotherapy alone [arm A] FOLFOX (± bev) plus SIRT using Y-90 resin microspheres [arm B] did not improve overall PFS (median 10.2 v 10.7 months arm A v B, HR: 0.93; 95% CI 0.77–1.12; p = 0.429). However, liver PFS by competing risk analysis was improved with the addition of SIRT (median 12.6 v 20.5 months in arm A v B, HR: 0.69; 95% CI 0.55–0.90; p = 0.002). The current analysis examines patterns of disease progression and potential impact on the primary study endpoint. Methods: Site and pattern (intra/extra-hepatic) of first progression, and whether progression was due to growth of existing lesions or the appearance of new lesions, was judged by an independent reader blinded to study arm. Results: From Oct 2006 to Apr 2013, 530 pts were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases at study entry; 292 (55%) were stratified to receive bev. As of 31 Jan 2015, the total number of patients with disease progression in arm A v B were 178 and 166, respectively. The site of first progression was more frequently in the liver (± other sites) in arm A v B (92.1% v 72.3%; p &lt; 0.001). Conversely, site of first progression was less frequent in the lung (± other sites) in arm A v B (19.1% v 42.8%; p &lt; 0.001). A higher proportion of first progression occurred in the liver alone in arm A v B (77.0% v 52.4%; p &lt; 0.001). Conversely, a lower proportion of first progression occurred only in non-liver sites, primarily lung, in arm A v B (7.9% v 47.7%; p &lt; 0.001). Of patients with first progression in the liver, a higher proportion occurred in existing liver lesions (± extrahepatic sites) in arm A v B (72.5% v48.2%; p &lt; 0.001). Conclusions: The addition of SIRT to FOLFOX chemotherapy alone (± bev) reduced the frequency at which first disease progression occurred in the liver. Where first progression did occur in the liver, the addition of SIRT led to this more frequently being due to the appearance of lesions not evident on baseline imaging. Clinical trial information: NCT00724503.

Image-guided stereotactic ablative radiotherapy for the liver: A safe and effective treatment

AimsStereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for inoperable patients or patients with irresectable liver tumors. Outcome and toxicity were evaluated retrospectively in this single-institution patient cohort. Patients and methodsBetween 2010 and 2014, 39 lesions were irradiated in 33 consecutive patients (18 male, 15 female, median age of 68 years). All the lesions were liver metastases (n = 34) or primary hepatocellular carcinomas (n = 5). The patients had undergone four-dimensional respiration-correlated PET-CT for treatment simulation to capture tumor motion. We analyzed local control with a focus on CT-based response at three months, one year and two years after treatment, looking at overall survival and the progression pattern. ResultsAll patients were treated with hypofractionated image-guided stereotactic radiotherapy. The equivalent dose in 2 Gy fractions varied from 62.5 Gy to 150 Gy, delivered in 3–10 fractions (median dose 93.8 Gy, alpha/beta = 10). The CT-based regression pattern three months after radiotherapy revealed partial regression in 72.7% of patients with a complete remission in 27.3% of the cases. The site of first progression was predominantly distant. One- and two-year overall survival rates were 85.4% and 68.8%, respectively. No toxicity of grade 2 or higher according to the NCI Common Terminology Criteria for Adverse Events v4.0 was observed. ConclusionSABR is a safe and efficient treatment for selected inoperable patients or irresectable tumors of the liver. Future studies should combine SABR with systemic treatment acting in synergy with radiation, such as immunological interventions or hypoxic cell radiosensitizers to prevent distant relapse.

Local Ablative Therapy of Oligoprogressive Disease Prolongs Disease Control by Tyrosine Kinase Inhibitors in Oncogene-Addicted Non–Small-Cell Lung Cancer

Many patients with oncogene-driven non-small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively. Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded. Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months. Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.

Hypofractionated image-guided breath-hold SABR (Stereotactic Ablative Body Radiotherapy) of liver metastases – clinical results

PurposeStereotactic Ablative Body Radiotherapy (SABR) is a non-invasive therapy option for inoperable liver oligometastases. Outcome and toxicity were retrospectively evaluated in a single-institution patient cohort who had undergone ultrasound-guided breath-hold SABR.Patients and methods19 patients with liver metastases of various primary tumors consecutively treated with SABR (image-guidance with stereotactic ultrasound in combination with computer-controlled breath-hold) were analysed regarding overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity.ResultsPTV (planning target volume)-size was 108 ± 109cm3 (median 67.4 cm3). BED2 (Biologically effective dose in 2 Gy fraction) was 83.3 ± 26.2 Gy (median 78 Gy). Median follow-up and median OS were 12 months. Actuarial 2-year-OS-rate was 31%. Median PFS was 4 months, actuarial 1-year-PFS-rate was 20%. Site of first progression was predominantly distant. Regression of irradiated lesions was observed in 84% (median time to detection of regression was 2 months). Actuarial 6-month-LC-rate was 92%, 1- and 2-years-LC-rate 57%, respectively. BED2 influenced LC. When a cut-off of BED2 = 78 Gy was used, the higher BED2 values resulted in improved local control with a statistical trend to significance (p = 0.0999). Larger PTV-sizes, inversely correlated with applied dose, resulted in lower local control, also with a trend to significance (p-value = 0.08) when a volume cut-off of 67 cm3 was used.No local relapse was observed at PTV-sizes < 67 cm3 and BED2 > 78 Gy. No acute clinical toxicity > °2 was observed. Late toxicity was also ≤ °2 with the exception of one gastrointestinal bleeding-episode 1 year post-SABR. A statistically significant elevation in the acute phase was observed for alkaline-phosphatase; in the chronic phase for alkaline-phosphatase, bilirubine, cholinesterase and C-reactive protein.ConclusionsA trend to statistically significant correlation of local progression was observed for BED2 and PTV-size. Dose-levels BED2 > 78 Gy cannot be reached in large lesions constituting a significant fraction of this series. Image-guided SABR (igSABR) is therefore an effective non-invasive treatment modality with low toxicity in patients with small inoperable liver metastases.

Continuation of EGFR/ALK inhibition after local therapy of oligoprogressive disease in EGFR mutant (Mt) and ALK+ non-small cell lung cancer (NSCLC).

7526 Background: This study aimed to investigate the benefits of local treatment of limited disease progression and continuation of crizotinib (C) or EGFR-TKI in patients with ALK+ or EGFR-Mt metastatic NSCLC, respectively. Methods: Patients with advanced ALK+ NSCLC treated with C (n=38) and EGFR-Mt NSCLC treated with EGFR TKIs (erlotinib or gefitinib) (n=27) were identified. Patients were evaluated for initial response, site of first progression (CNS or extra CNS (eCNS)) and median progression free survival (PFS1). A subset of patients with limited sites of progression (oligoprogressive disease) suitable for local therapy received either radiation or surgery to these sites and continued on the same TKI. The subsequent pattern of progression and median progression free survival from the time of first progression (PFS2) were recorded. Results: In 38 ALK+ patients, PFS1=9.0 months on C. In 27 EGFR-Mt patients, PFS1=13.8 months on EGFR-TKI. CNS was the first site of progression in 13/28 (46%) of ALK+ patients and 5/23 (22%) EGFR-Mt patients. 25 of 51 patients who progressed (49%) were deemed suitable for local therapy (15 ALK+, 10 EGFR-Mt; 24 with radiotherapy (Body: 3 XRT, 9 SBRT; CNS: 7 WBRT, 5 SRS), 1 with surgery (adrenalectomy)) and continuation of the same targeted therapy. 19/25 patients progressed post local therapy, median PFS2 = 6.2 months. In patients who progressed at PFS1 only in the CNS, there was a trend to longer PFS2 than patients who progressed at PFS1 in eCNS (7.1 months vs 4.0 months, p=0.26). 60% who progressed only in the CNS at PFS1, progressed eCNS at PFS2 (n=10). Conclusions: Progression of oncogene addicted NSCLC on relevant targeted therapies is often suitable for local therapy (oligoprogressive disease). Continuation of the targeted therapy following local therapy is associated with &gt;6 months of additional disease control. [Table: see text]

WJOG6110B (ELTOP): Randomized phase II trial comparing trastuzumab plus capecitabine (HX) and lapatinib plus capecitabine (LX) in HER2-positive metastatic breast cancer patients previously treated with trastuzumab and taxanes.

TPS659 Background: In patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and taxanes, there are now two standard strategies: trastuzumab beyond progression or switch to lapatinib. A randomized trial comparing trastuzumab plus capecitabine (HX) and capecitabine alone (X) after first-line trastuzumab-based chemotherapy (GBG-26) showed that HX was superior to X in terms of time to progression (TTP). Another randomized trial comparing lapatinib plus capecitabine (LX) and X in patients previously treated with anthracyclines, taxanes, and trastuzumab (EGF100151) showed that LX was superior to X in terms of TTP. To evaluate which strategy is better, we are conducting an open-label, randomized phase II trial comparing HX and LX. Methods: Primary endpoint is progression-free survival, and secondary endpoints are overall response rate, overall survival, proportion of patients progressing brain metastases as site of first progression, and safety. Major eligibility criteria include: (1) HER2-positive MBC, (2) previously treated with taxanes, (3) disease progression or distant relapse while receiving trastuzumab, (4) previously untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab, (5) previously treated with no more than two chemotherapy regimens for MBC, (6) no symptomatic brain metastases (asymptomatic brain metastases are allowed), and (7) baseline left ventricular ejection fraction ≥50%. Patients in the HX arm receive capecitabine 2,500 mg/m2/day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and 6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive capecitabine 2,000 mg/m2/day on days 1 to 14 plus lapatinib 1250 mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are also performed to explore predictive factors of trastuzumab or lapatinib efficacy. We are investigating biomarkers related to HER family and other receptors, PI3K/Akt pathways, ligands, FcγR, circulating tumor cells, and so on. This study has just begun and 7 of planned 170 patients have been enrolled.

Trastuzumab-resistant HER2-positive metastatic breast cancer: Comparing results of lapatinib and capecitabine in brain and other metastatic sites.

e11505 Background: Trastuzumab, anthracycline, and taxane resistant HER2-positive metastatic breast cancer has poor prognosis. Progression in brain metastasis (BM) commonly leads to difficult diagnostic interpretation and treatment decisions, poor quality of life, and death. Methods: Consented patients (pts) with HER2-positive metastatic breast cancer, ECOG ≤2, with resistance to trastuzumab, taxane, and anthracyclines, were recruited for treatment with daily lapatinib (L) (1,250 mg daily) and capecitabine (C) (2,000 mg/m2/day days 1-14) in a 21 day cycle. Progression was evaluated by RECIST and statistics by SPSS. Results: We enrolled 10 pts (median age 44), median follow up was 19.51 months (M). One patient had grade 3 toxicity due to C and was kept with L only; no other patient discontinued L nor C due to toxicity. Nine (90%) pts had ≥2 metastatic sites, one pt had BM only, and 6 pts had BM in addition to other sites. Median time to progression (TTP) was 9.10 M for the 10 pts, 13.86 M for BM as site of first progression, and 5.90 M for non-BM progression (p<0.05). BM was the most common site for first progression, seen in 4 pts. There was no new BM lesion during treatment. Overall BM response to Tx was 50% (1 complete response, 2 partial responses). In all 4 patients that progressed in central nervous system, head NMR showed enlarged metastatic lesions with central liquefied images, and were interpreted initially as radio/chemo necrosis. Two pts had neurological symptoms and discontinued L and C. The last two pts that progressed in brain had their metastatic images interpreted as necrosis also. However, specific NMR vascular analysis revealed higher perfusion/permeability image patterns, interpreted as caused by tumor activity. They went to BM surgical resection and histology showed tumor cells and 40% of necrosis. Both patients are well and without signs or symptoms after surgery. Conclusions: Brain was the most common metastatic site in this pts, and BM had a longer TTP than the other metastasis. Surgical removal of BM appears to help patients and should be considered in earlier stage of enlargement of lesions. NMR perfusion-permeability studies may facilitate medical decisions. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline

Functional and clinical outcomes of limb-sparing therapy for pediatric extremity sarcomas

Purpose: To determine the clinical and functional outcomes of children undergoing limb-sparing therapy for extremity sarcomas. Methods and Materials: We retrospectively reviewed 30 patients, age ≤ 21 years, who were treated between l979 and l998 with external beam radiotherapy as a component of limb-sparing therapy for primary sarcomas of the extremity at UCSF. Included were patients for whom complete follow-up and functional outcome assessments were available. We assessed the patterns of failure, overall survival, disease-free survival, local control, and limb function. Results: At a median follow-up of 3 years, 12 of the 30 patients recurred: 3 locally, 8 distantly, and 1 with synchronous local and distant disease as site of first progression. Eighteen patients were alive with no evidence of disease. The median overall survival was 10 years, with a median disease-free survival of 8 years. Functional outcome assessment revealed 15 patients retained excellent, 12 good, 1 fair, and 2 poor limb function. Conclusion: In pediatric patients receiving limb-sparing therapy, 90% maintained excellent or good limb function without compromising survival, demonstrating the validity of limb preservation in children with extremity sarcomas.