2nd Line Setting Research Articles

PCN145 - COST-EFFECTIVENESS OF NINTEDANIB FOR THE TREATMENT OF NON-SMALL LUNG CANCER IN PORTUGAL

Lung cancer is the main cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) representing approximately 85% of all cases. Nearly 30-40% of NSCLC patients have metastatic disease at diagnosis (mNSCLC). Five-year survival rates for mNSCLC are below 36%. This study aimed to assess the cost-effectiveness of nintedanib for the treatment of adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy in Portugal. A survival model was developed to represent the natural history of NSCLC for a lifetime horizon. Best supportive care (BSC) + docetaxel were set as the comparator. Efficacy and safety were derived from a phase III, randomised, double-blinded clinical trial (LUME-Lung 1) which compared nintedanib+docetaxel to placebo+docetaxel. Parametric survival analyses were performed and best fitting survival function was selected using Akaike's Information Criterion. Costs were derived from public sources. A 5% annual discount rate was adopted for costs and effects. Results were expressed in incremental costs per life year (LY) and quality-adjusted life years (QALY). On average, nintedanib + docetaxel is expected to increase mNSCLC undiscounted life expectancy by 0.39 LYs versus BSC + docetaxel (21.7 versus 17.0 months). Nintedanib is expected to augment overall treatment costs by 1,482€/patient (discounted) mainly related to higher drug costs and higher patients’ survival, corresponding to an incremental CE ratio of 4,718€/LY and 7,192€/QALY. The probabilistic sensitivity analysis performed revealed LYs gains ranging between -0.21 and 0.82 and incremental costs ranging between -4,493€ and 6,544€. The sensitivity analysis confirmed a 99% probability of nintedanib to be a cost-effective strategy at a threshold of 20,000€/LY. In the 2nd mNSCLC line setting, nintedanib is expected to provide a clinically meaningful life expectancy increase at an incremental cost per life year gained within an acceptable range.

Abstract 916: A screen to target EGFR (C797S) in osimertinib-resistant lung cancer identifies brigatinib-based combinations that synergistically inhibit cell growth

Abstract Up to 20% of non small-cell lung cancers are driven by activating mutations in EGFR (EGFRm). While EGFR tyrosine kinase inhibitors (TKIs) have proven highly effective in the clinic (e.g. gefitinib in first line EGFRm and osimertinib in T790M post-TKI resistance), acquired resistance mechanisms present an obstacle to curing EGFR-driven disease. To-date, approximately 20% of osimertinib-resistant cases in the 2nd line setting are EGFRm/T790M/C797S, and there is currently no approved therapy for these “triple-mutant” (TM) patients. We have obsrerved that the ALK inhibitor brigatinib shows moderate, equipotent activity against both EGFR-TM and the single activating mutant. We used this information to screen a panel of compounds to identify brigatinib-based combinations that could effectively target EGFR-TM-expressing cells. Among the most potent combination partners were selumetinib and other inhibitors of the MAP kinase pathway. These agents were able to synergistically impair growth of TM cells when combined with brigatinib in vitro, and accordingly show prolonged suppression of downstream pathway biomarkers in combination- vs. brigatinib monotherapy-treated cells. Further, we have shown effective combinations can dramatically enhance apoptotic cell death compared to brigatinib treatment alone. Critically, neither monotherapy treatment with effective combination partners, nor combinations based on osimertinib showed growth inhibition in the EGFR triple-mutant setting. Taken together, these data suggest novel therapeutic strategies for patients in this critical area of unmet need that warrant further preclinical testing. Citation Format: Matthew J. Martin, Nicolas Floc'h, Chrysiis Michaloglou, M Raymond Finlay, Richard A. Ward, Paul D. Smith, Darren A. Cross. A screen to target EGFR (C797S) in osimertinib-resistant lung cancer identifies brigatinib-based combinations that synergistically inhibit cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 916.

Tumor mutational burden assessed by a targeted NGS assay to predict benefit from immune checkpoint inhibitors in non-small cell lung cancer.

e15075Background: Immune checkpoint inhibitors (ICI) improve overall survival in non-small cell lung cancer (NSCLC) in the 2nd-line setting and lead to prolonged disease control in a subgroup of pa...

Dynamic monitoring HER2 amplification of circulating DNA in metastatic colorectal cancer patients treated with cetuximab.

714 Background: Addition of cetuximab has shown clinical benefit in RAS and BRAF wild-type (wt) patients with metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 2 ( HER2) amplification was reported to be one of the resistance mechanisms to cetuximab. We investigated whether monitoring of HER2 amplification in circulating DNA allows early detection of progression and informs about resistance to cetuximab. Methods: We analyzed HER2 amplification in circulating DNA by 8 week-interval using droplet digital polymerase chain reaction (ddPCR) from 30 RAS and BRAF wt patients, who progressed after failure of cetuximab-containing regimens between Jul 2015 and Jun 2017. Results: 16.7% (5/30) of patients exhibited dynamic fluctuations of HER2 amplification in plasma, one of whom was found to be positive for HER2 amplification in matched tumor tissue sample using FISH. Two patients had HER2 and c-MET co-amplification. All 5 primary sites were left side, 4 rectums and 1 descending colon. 3 patients received cetuximab as first line therapy, whereas 2 patients in the 2nd line setting. Among these 5 patients, changes in circulating DNA levels showed good agreement with changes in tumor volume. Furthermore, quantifications of HER2 amplification showed obvious increase with an average lead time of 2 months compared with CT documented progress. But interestingly, there was no difference in progression-free survival (PFS) between these 5 patients and the others without HER2 amplification (p > 0.05). Conclusions: Plasma HER2 amplification detected by ddPCR was showed dynamic changing over time and would predict resistance to cetuximab-containing treatment. Average 2 months lead time was observed and need to validate in the further study.

P1.15-009 Safety and Efficacy of Nab-Paclitaxel Monotherapy as 2nd or Later Line Setting in Pts with Extensive SCLC, a Phase II Single Arm Study (NCT02262897)

P1.15-009 Safety and Efficacy of Nab-Paclitaxel Monotherapy as 2nd or Later Line Setting in Pts with Extensive SCLC, a Phase II Single Arm Study (NCT02262897)

MTE 22.02 Treatment Options in Advanced Non-Small Cell Lung Cancer (NSCLC) in the Elderly: An Evolving Landscape

MTE 22.02 Treatment Options in Advanced Non-Small Cell Lung Cancer (NSCLC) in the Elderly: An Evolving Landscape

Abstract CT155: Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC)

Abstract Introduction: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) delivering SN-38, a topoisomerase-1 inhibitor, to mSCLC cells expressing Trop-2. We are studying the safety/tolerability and efficacy of IMMU-132 in patients with relapsed/refractory mSCLC who had received a platinum-containing first-line regimen. Experimental Procedure: Patients received 8 or 10 mg/kg IV IMMU-132 on days 1 and 8 of repeated 21-day cycles. Objective tumor response (ORR) was determined by RECISTv1.1 in patients receiving at least one treatment cycle, and progression-free survival (PFS) and overall survival (OS) in all patients by Kaplan-Meier methods. (ClinicalTrials.gov, NCT01631552) Summary of New Unpublished Data: A total of 53 patients (23/30 M/F, median 63 years old) with 1-7 (median 2) prior lines of therapy were enrolled between November, 2013 and June, 2016. Immunohistochemistry of evaluable archival tumor specimens for Trop-2 expression (N=26) showed 92% positivity (61% moderately to strongly positive). They received up to 32 treatment cycles (median 5); the most frequent Grade >3 adverse events were neutropenia (34%), fatigue (13%) and diarrhea (9%). Four patients did not complete one cycle of treatment. In the other 49 patients (14 at 8 mg/kg, 35 at 10 mg/kg), there were 7 confirmed PRs and 21 SDs as best response. The resulting ORR rate was 14% (7/49), with a median duration and time-to-progression of a response of 4.0 and 7.6 mos, respectively, and the clinical benefit rate (PR+SD >4 mos) was 35% (17/49). The ORR rate was similar in pts who were sensitive (>3 mos response) or resistant (<3 mos) to 1st-line therapy [13% (3/23) vs 15% (4/26), respectively]. In 2nd-line setting, IMMU-132 had a confirmed ORR rate of 14% (3/21), and a clinical benefit rate of 38% (8/21). This compares well to recent results with topotecan having an ORR of 13-16% in 2nd-line. Comparing dose levels, ORR was 17% (6/35) with 10 mg/kg vs 7% (1/14) with 8 mg/kg, with little difference in toxicity. Median PFS and OS in all 53 patients was 3.7 mos (95% CI, 2.0 - 4.3) and 7.0 mos (95% CI, 5.5 - 8.3), respectively, and included 6 long-term survivors (12.7 - 25.4 months). No antibody response to the ADC or antibody was detected despite multiple therapy cycles. Conclusion: These interim results demonstrate encouraging activity in patients with late-stage mSCLC having a high expression of Trop-2. Even after failing 1st-line platinum chemotherapy or 2nd-line topotecan therapy, IMMU-132 showed promising activity, and has a manageable toxicity profile. IMMU-132 given at 10 mg/kg on day 1 and 8 of a 3-week cycle was selected for further clinical evaluation in this population. Citation Format: Jhanelle E. Gray, Rebecca S. Heist, Alexander N. Starodub, D. Ross Camidge, Ebenezer Kio, Gregory Masters, W. Thomas Purcell, Michael J. Guarino, Jamal Misleh, Charles J. Schneider, Bryan J. Schneider, Allyson J. Ocean, Tirrell Johnson, Leena Gandhi, Kevin Kalinsky, Serengulam V. Govindan, Pius Maliakal, Boyd Mudenda, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT155. doi:10.1158/1538-7445.AM2017-CT155

Abstract CT096: Phase 1b study of ramucirumab (RAM) in combination with fluoropyrimidine and platinum-based agents in Japanese patients (pts) with metastatic gastric/gastroesophageal junction adenocarcinoma (mGC)

Abstract Background: Fluoropyrimidine and platinum-based regimens have been established as a global standard of care, including Japan, for the 1st-line treatment of pts with mGC. RAM is a human IgG1 antibody against VEGFR-2. In the 2nd-line setting, 2 global phase 3 studies of RAM alone (REGARD) and RAM + paclitaxel (RAINBOW), demonstrated significant improvement in survival compared to placebo and paclitaxel + placebo, respectively. The subset analysis of the RAINBOW study suggested that higher RAM exposures were associated with improved survival outcome. In this study, safety, tolerability, pharmacokinetics (PK) and efficacy of a new RAM dosing schedule in combination with 3 fluoropyrimidine and platinum-based regimens in the 1st-line setting were evaluated in Japanese pts with mGC. Patients and Methods: This was a multicenter, single-arm, phase 1b study in mGC pts in the 1st-line setting. On each cycle, pts received 8 mg/kg RAM at days 1 and 8, every 3-weeks (q3w), in combination with XP q3w: capecitabine (2000 mg/m2, days 1-14, PO) + cisplatin (80 mg/m2, day 1, IV); SP every 5-weeks (q5w): S-1 (80 mg/m2/day, days 1-21, PO) + cisplatin (60 mg/m2, day 8, IV); or SOX q3w: S-1 (80 mg/m2/day, days 1-14, PO) + oxaliplatin (100 mg/m2, day 1, IV). The primary objective was to confirm safety and tolerability; secondary objectives were to evaluate PK and anti-tumor response. Results: 18 pts, 6 in each cohort, were treated. Pts received RAM for median 23.4 weeks (min 2.0 - max 69.0). Across all cohorts, only 1 dose-limiting toxicity was observed during the 1st cycle (grade 3 enterocolitis), and resolved after treatment discontinuation. Three treatment-related serious adverse events (AE) were observed: decreased appetite (n=1), pelvic venous embolism (n=1) and enterocolitis (n=1). Treatment-related AE of any grade included neutropenia (n=14), decreased appetite (n=12), constipation (n=11), nausea (n=11), and hypertension (n=9). Compared to the currently approved 8 mg/kg every 2-weeks (q2w) regimen, the new dose regimen used in this study (8 mg/kg days 1 and 8 q3w) has produced higher mean trough concentrations of RAM. Disease control rate (DCR) was 100% and overall response rate (ORR) was 45% in patients with measurable lesions (n=11). Conclusion: The new scheduling regimen of RAM (8 mg/kg, days 1 and 8, q3w) in combination with either of XP, SP or SOX, was tolerable in Japanese mGC pts in the 1st-line setting. Currently, a global phase 3 study of XP and an Asian randomized phase 2 study of SOX are ongoing to evaluate potential benefits of adding RAM to current standard 1st-line therapies. (NCT02359058) Citation Format: Shigenori Kadowaki, Kohei Shitara, Daisuke Sakai, Tomohiro Nishina, Reigetsu Yoshikawa, Yongzhe Piao, Akichika Ozeki, Koichi Inoue, Kei Muro. Phase 1b study of ramucirumab (RAM) in combination with fluoropyrimidine and platinum-based agents in Japanese patients (pts) with metastatic gastric/gastroesophageal junction adenocarcinoma (mGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT096. doi:10.1158/1538-7445.AM2017-CT096

Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial.

LBA8507 Background: To date, no treatment is recommended in MPM pts progressing after 1st-line pemetrexed-platinum doublet. Disease control rate (DCR) is <30% with all drugs tested in 2nd-line setting. Preliminary results suggested possible activity of anti-PD-1 mAb in 2nd/3rd-line, opposed to single agent anti-CTLA-4 mAb. Therefore anti-PD1 mAb efficacy deserves confirmation, and anti-PD-1 + anti-CTLA-4 combination value is currently unknown in MPM. Methods: In this multicenter randomized non comparative phase 2 trial, eligible pts had age>18, PS 0-1, histologically proven MPM relapsing after 1 or 2 prior lines including pemetrexed/platinum doublet, measurable disease. Randomized pts (1:1) received Nivo 3 mg/kg q2w, or Nivo 3 mg/kg q2w + Ipi 1 mg/kg q6w, until progression or unacceptable toxicity. Primary endpoint was DCR at 12 weeks with a blinded independent central review (BICR). 114 patients were to be randomized (with 108 eligible), with one-step Fleming procedure, H0 P<20% vs H1 P>40%, with 95% power, 5% one-sided a-risk: ≥17 failure-free pts had to be observed at 12 weeks in either arm, to conclude to the activity of the corresponding regimen. Results: From March to August 2016, 125 pts were enrolled in 21 centers. Males: 80%, median age: 71.8 years (range 32.5-88.1), PS 1: 62.4%, epithelioid 83.2%, 1 previous line: 69.6%; 70% of pts received ≥ 3 cycles of either treatment. Twelve weeks-DCR assessed by BICR in the first 108 eligible pts was 42.6% [IC95%: 29.4-55.8%] with Nivo (n=23/54), and 51.9% [38.5-65.2%] with Nivo+Ipi (n=28/54). ORR was 16.7% [6.7%-26.6%] with Nivo (n=9/54), and 25.9% [14.2-37.6%] with Nivo+Ipi (n=14/54). All grade/G3-4 toxicities were slightly increased in the combo arm (86.9%/16.4%) vs Nivo alone (77.8%/9.5%); 3 treatment-related deaths were observed in the combo arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). Full QoL, PFS and OS data will be presented at 2017 ASCO meeting. Conclusions: Both Nivo and Nivo+Ipi arms reached their endpoint in 2nd/3rd-line MPM pts, suggesting that immunotherapy may provide new options for these pts. Clinical trial information: NCT02716272.

P-206 - Expanded analysis of mFOLFIRINOX as second-line chemotherapy in pancreatic adenocarcinoma

Introduction: Folfirinox is a highly effective first-line chemotherapy regimen in patients with good performance status. The landscape in second-line therapy is, however, less clear with many oncologists feeling uncomfortable using Folfirinox based upon toxicity data from the original ACCORD study. Our aim is to assess our single institution’s experience in the use of the more tolerable mFOLFIRINOX in the 2nd line setting. Since our previous publication, we have gained additional experience with more patients receiving this regimen as second-line therapy. At the time of writing, we have used Folfirinox in 40 patients up to age 85 years. Methods: 40 patients who had previously received gemcitabine-based chemotherapy for pancreatic adenocarcinoma were identified from our database. The records were then examined to determine treatment outcomes and toxicities together with dose intensities delivered. Results: Out of 40 patients with an age range of 27 to 85, 14 were aged over 70. 2 patients had received single agent gemcitabine and 38 gemcitabine in combination with nab-paclitaxel. Dose intensity was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-FU and 68% for infusional 5FU. A 10% grade 3 toxicity rate was observed with modifications mainly for neuropathy from oxaliplatin. Significantly, we noted that overall survival in this group ranged from 5-67 months (median 23 months for locally advanced/15 months for metastatic). More than half of the patients received a minimum of 6 cycles, with 20 patients receiving greater than 6 cycles of treatment and 8 patients more than 12 cycles. One patient has received 70 cycles with excellent control of ascites and peritoneal disease. Conclusion: Our single institution experience continues to demonstrate the safety, tolerability and efficacy of mFolfirinox as a second-line therapy after gemcitabine failure. A formal study using mFOLFIRINOX as the interventional arm would be extremely useful in determining whether this approach shows merit in a more rigorous scientific setting.

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer

Objective: The aim of this study was to evaluate the efficacy and safety of combining irinotecan, bevacizumab, and cetuximab/panitumumab as a 4th-line treatment in patients with metastatic colorectal cancer. Methods: All patients had KRAS wild-type metastatic colorectal cancer and had previously received fluoropyrimidine, oxaliplatin, irinotecan, and cetuximab/panitumumab in a 1st, 2nd, and 3rd line setting. Most patients had previously received bevacizumab as well. All patients had progressed within 3 months after the last given treatment before starting the triple combination therapy every second week. Results: Sixty-three patients were evaluated. The triple combination therapy was well tolerated. The median progression-free survival was 6.1 months, and the median overall survival was 11.9 months. Four patients (6%) obtained a partial response, and 40 (63%) had stable disease. Conclusion: The combination of irinotecan, bevacizumab, and cetuximab/panitumumab is safe and shows a toxicity profile corresponding to what is expected from the agents alone. The results indicate that the combination in the 4th line may result in a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer.

Modified FOLFIRINOX (mFOLFIRINOX) as second-line chemotherapy in pancreatic adenocarcinoma.

e15747 Background: FOLFIRINOX is a highly effective combination chemotherapy regimen with the reputation of only being tolerable to young patients with good performance status. As the original ACCORD study was carried out at specific French university hospitals with patients performance status 0 or 1 many oncologists feel uncomfortable administering mFOLFIRINOX as a second-line therapy. We have previously reported our experience in 24 patients ages 27 - 84 where we concluded that dose modified FOLFIRINOX can be safely administered to elderly patients with appropriate initial dose reductions and subsequent escalation. There is a lack of consensus on a standard second-line regimen for metastatic pancreatic cancer. We conducted a review of dose intensity and outcome for all patients treated with 2nd or 3rd-line mFOLFIRINOX for pancreatic adenocarcinoma at St John of God Hospital, Subiaco, Western Australia in order to assess efficacy and tolerability Methods: Electronic records were used to identify 35 patients who had received 1st-line gemcitabine-based chemotherapy who then went on to receive 2nd or 3rd line mFOLFIRINOX. Case files, laboratory and radiology records were then examined to determine outcomes and toxicities. Results: 35 patients were identified with an age range of 27- 85, both locally advanced and metastatic disease, with 12 over the age of 70. All patients except 2 had gemcitabine plus abraxane in the first line setting. Dose intensity was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-FU and 68% fir infusional 5FU. Toxicity was acceptable with a grade 3 toxicity rate of 10%. Overall survival in this group ranged from 5-67 months (median 23 months for locally advanced / 15 months for metastatic). Notably, 20 patients received greater than 6 cycles of treatment and 8 patients received more than 12 cycles. One patient has received 70 cycles. Conclusions: Our experience demonstrates the safety, tolerability and efficacy of mFolfirinox as a second-line therapy after gemcitabine failure. The disease control rate, even with the reduction in dose intensity, suggests that modified Folfirinox should be formally tested in the 2nd line setting in a clinical trial.

Radiomic biomarkers for the prediction of immunotherapy outcome in patients with metastatic non-small cell lung cancer.

e14520 Background: PD-1 checkpoint inhibitors have recently been approved for the treatment of patients with metastatic NSCLC. Predicting to what extent patients will benefit from these treatments is challenging. Research on predictive biomarkers focus on genetic and histological markers from biopsies, necessarily limited to parts of the tumor. Radiomics is a novel approach to quantify characteristics of the tumor on medical imaging, which may have potential value as non-invasive biomarkers. In this study, we explored the value of radiomic data from primary tumors to predict overall survival (OS) in patients with metastatic NSCLC treated with Nivolumab Methods: We retrospectively selected 64 metastatic NSCLC patients treated in 2ndline setting with Nivolumab (240 mg q 2 weeks until progression). Inclusion criteria were: primary tumor in situ with contrast enhanced CT scan (thorax abdomen; slice thickness ≤3mm) within 6 weeks before the start of the treatment. Exclusion criteria were: presence of atelectasis or fusion with other structures and presence of multiple lung lesions at first scan. A certified radiologist delineated the tumors on CT from which we extracted 1696 Radiomic features. Unsupervised feature selection was performed. Multivariate Cox Regression was used to model the OS based on the selected features, as well as, histopathological type (adeno vs squamous), age at the start of the treatment, and extent of metastatic disease ( < 5, 5–10, or > 10 metastasis) Results: The selection resulted in three textural features derived from a Laplacian of Gaussian (LoG): regions dissimilarity (GLRLM_rlnun), entropy (GLSZM_ze), and uniformity. The resulting model was significant (p = 0.005). Both regions dissimilarity (HR = 0.11, 95% CI 0.03–0.46, p = 0.002) and entropy (HR = 0.20, 95% CI 0.06–0.67, p = 0.009) were significant predictors of OS. Subtype and disease extent were close to significance (p = 0.099) Conclusions: Results indicate that more heterogeneous tumors with irregular patterns of intensities showed better OS. The availability of CT scans makes Radiomics a potentially valuable adjunct to other clinical biomarkers. Further validation of our findings in larger cohorts are warranted

Treatment sequences in non-small cell lung cancer in the United States from 2014-2016.

237 Background: A number of important advancements in the treatment of metastatic non-small cell lung cancer (mNSCLC) have increased and diversified options for improved patient care based on individual characteristics. The ability to tailor therapy increases the challenges related to appropriate treatment sequencing. This study was designed to describe these emerging treatment patterns following the approval of novel targeted agents. Methods: Flatiron Health OncoEMR, a nationally-representative electronic medical records database in the US, was used to evaluate treatment patterns by histology (squamous and nonsquamous). Eligible patients were 18+ years of age who initiated 2ndline therapy for mNSCLC from Dec 2014-Jul 2016. Descriptive statistics were used to characterize the clinical and demographic characteristics of the study population, treatments used by line of therapy, and treatment sequencing. Analyses were conducted using SAS version 9.2. Results: A total of 3498 eligible patients were included in this study: 51.3% male; mean age 66.6 years; 65% white; 25% squamous/70.7% nonsquamous (4.3% not specified); and 93% were treated at community practices. ALK testing was performed on 20.0%/74.8%, EGFR testing on 21.5%/79.8%, and PDL-1 on 8.6%/9.7% of patients with squamous/nonsquamous tumors, respectively. Single-agent PDL-1 inhibitors were used by 54.2% of squamous and 35.2% of nonsquamous patients in the 2nd-line setting; however, there were more than 35 (squamous) and 64 (nonsquamous) unique first-line regimens prior to single-agent PDL-1 treatment. Other 2nd-line regimens included pemetrexed (24.9% of nonsquamous patients) and gemcitabine (18.4% of squamous patients), which were preceded by 70 and 48 unique first-line regimens, respectively. Conclusions: There is interest in understanding treatment sequencing to identify the optimal sequence of care for patients with NSCLC; however, there was considerable heterogeneity in sequencing. Since few patients follow any similar trajectory of care, comparative effectiveness research will be challenged to appropriately balance groups due to insufficient patient numbers in any specific treatment sequence.

Abstract PL1: Management of metastatic ER+ breast cancer

Abstract Estrogen receptor positive (ER+) metastatic breast cancer (MBC) is the most common form of the disease, and its prognosis and outcome depends on a variety of clinical factors relating to disease free interval (DFI), response to prior adjuvant therapy, distribution of metastatic disease, and the intrinsic biological subtype of the ER+ tumor. The goals of treatment are to provide effective anti-cancer therapy that will control cancer growth, whilst at the same time maintaining quality of life. International guidelines recommend that for postmenopausal women with ER+ MBC endocrine therapy should be the 1st-line approach for the majority of patients, unless patients have a symptomatic visceral crisis that requires cytotoxic chemotherapy. Aromatase inhibitors (AIs) have been the standard of care with a median progression-free survival (PFS) of 10-13 months reported in previous studies. Recent 1st-line trials aimed at improving upon AIs have investigated either the selective estrogen receptor downregulator (SERD) fulvestrant, or targeted combination of AIs with cyclin dependent kinase (CDK 4/6) inhibitors. While some trials have seen benefit for fulvestrant over AIs in subgroups of endocrine therapy naïve patients (SWOG-O226) or those with non-visceral metastases (FALCON), significant improvement across all subgroups have been reported in two separate phase III trials for both palbociclib (PALOMA-2) and ribociclib (MONALEESA-2) when combined with the AI letrozole. Although it would appear that both endocrine-sensitive and endocrine-resistant disease benefit from combined AI + CDK 4/6 inhibitor therapy, one of the key issues in routine clinical practice is whether all 1st line patients require this approach. In the 2nd-line setting following progression on non-steroidal AIs, further endocrine monotherapy with either the steroidal aromatase inactivator exemestane or the SERD fulvestrant will yield a median PFS of only 3-4 months (EFECT, SOFEA). Much laboratory and translational research has explored mechanisms of resistance to AIs, and trials have since shown that median PFS can be improved to 9-11 months using targeted combinations of either exemestane with the mTOR antagonist everolimus (BOLERO-2), or fulvestrant together with the CDK 4/6 inhibitor palbociclib (PALOMA-3). Studies in endocrine resistance have looked at the impact of acquired key mutations detected in circulating tumour DNA (ctDNA) (ie. ESR1 or PIK3CA) on endocrine responsiveness, and how these evolve during therapy. Likewise, other signalling pathways have been implicated in causing endocrine resistance, and further combination trials are ongoing. While rapid and real progress has been made in ER+ MBC, integrating these novel, well tolerated, targeted combinations into the treatment algorithm of ER+ MBC is a current challenge. In particular, it will be crucial to understand the optimal sequence of endocrine based treatments that will keep patients free of disease progression for as long as possible with a good quality of life. Citation Format: Johnston RD. Management of metastatic ER+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PL1.

Left versus right sided colorectal cancer: Teasing out drivers of disparity in outcomes in metastatic disease.

682 Background: Patients (pts) with metastatic colorectal cancer (mCRC) arising from a right sided colon cancer (RCC) have an inferior survival versus pts with a left sided primary (LCC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively collected data on consecutive mCRC pts at 32 sites (Australia and Hong Kong) from July 2009. LLC were defined as those distal to the splenic flexure. We analysed patient, tumour, treatment and outcome data. Results: Of 1763 patients, median age 67 years (range 18 – 100), 1201 patients (68.1%) had a LCC. RCC were more common in pts ≥ 70 years old (53.9% vs 38.5%, p < 0.01) and females (50.7%, p < 0.01). Where tested, KRAS (50.9% vs 41.5%, p < 0.01) and BRAF (19.1% vs 6.4%, p < 0.01) mutations were more common in RCC. Where tested, dMMR was more common in RCC (11.0% vs 3.2%, p < 0.01). Pts with a RCC more often had peritoneal metastases (25.9% vs 12.5%%, p < 0.01) and were less likely to have liver metastases (69.8% vs 77.9%, p < 0.01) or resection of metachronous metastases (31.8% vs 43.6%, p < 0.01). LCC more commonly received chemotherapy in the 1st (86.1% vs 80.3%, p = 0.02) and 2nd (49.7% vs 43.0%, p = 0.04) line setting. There was no difference in ECOG performance status or co-morbidity for LCC vs RCC. Overall survival for pts with a RCC was 20.6 months vs 27.9 months for LCC L-sided tumours (HR 1.395, p < 0. 0001). Conclusions: Our data confirms that pts with mCRC arising from a RCC have an inferior survival. This appears multifactorial due to associations with adverse clinical and molecular features, metastatic pattern, and less therapy, some of which are related. A multivariate analysis is being performed.

SC04.03 Sequencing of EGFR Tyrosine Kinase Inhibitors

Treatment of EGFR-mutant (EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumor shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ∼ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhi bit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors (EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473-481. 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6. 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564. 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov 2015;5(7): 713-22. 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694-6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR. EGFR TKI, Resistance, Sequence

LBA19_PR - CNS tumours The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas

BRAF V600 mutations are present in 15%-20% patients (pts) with pediatric low-grade gliomas (pLGG). Relative to pts with BRAF V600–wild type pLGG, pts with BRAF V600E–mutant pLGG had poor survival and lower objective response rates (ORR) to initial (29%) and 2nd-line (11%) chemotherapy (Lassaletta A, ASCO 2016). There remains a need for improved treatment options for this pLGG subgroup. Dabrafenib is a potent and selective inhibitor of the V600–mutant form of the BRAF kinase. We report the results of the first study of dabrafenib in pediatric pts with BRAF V600–mutant recurrent or progressive LGG. Thirty-two pts aged 2-17 y with BRAF V600–mutant relapsed or refractory LGG were enrolled Dec 2013 to Jul 2015 across 4 dose levels of dabrafenib monotherapy up to and including the recommended phase 2 dose (RP2D; 4.5 mg/kg/day in pts ≥ 12 y, 5.25 mg/kg/day in pts < 12 y, divided into 2 equal doses per day [Kieran MW, ASCO 2015]). The results presented are from all 32 pts with pLGG (15 pts enrolled into the dose-finding and 17 pts treated after determination of the RP2D). Overall, 24 pts were treated at the RP2D. Twenty-two of the 32 pts remained on study as of April 2016. Adverse events were generally similar to those observed in adults, with frequent low-grade pyrexia, vomiting, fatigue, headache and rash. There have been no reports of cutaneous squamous cell carcinoma. The most frequent grade 3 or 4 AE was pneumonia, in 3 pts. 1 pt experienced a significant allergic reaction on day 2 of dosing and again upon rechallenge and was discontinued from study. Independent confirmed overall response by RANO criteria was 2 CRs and 11 PRs in this 2nd-line setting (N = 32, ORR 41% [95% CI, 24%-59%]), with a median duration of response of 11 months (8 responders ongoing). There were an additional 13 pts (41%) with SD of 6 months or greater duration (11 ongoing). Investigator confirmed overall response was 1 CR and 22 PRs (ORR 72% [95% CI, 53%-86%]). Targeted therapy using dabrafenib showed promising activity, with an independently confirmed ORR of 41%, and was well tolerated in this population with recurrent or progressive BRAF V600–mutant pLGG, comparing favorably to historical data.

Abstract P4-13-20: Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution

Abstract Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months. Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines. Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5). Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously. Baseline Characteristics and treatments (n=70)Characteristic(n)(%)Age Median56 Range27-83 Gender Female70100.0Male00.0Race Black1014.3White5477.1Other68.6Ethnicity Non Hispanic6694.3Hispanic45.7ER/PR status ER and PR negative2738.6ER and/or PR positive4361.4Type of disease Non visceral1622.9Visceral5477.1Visceral CNS2130.0Anti-HER2 in early stage Yes2941.4No4158.6Line of therapy 3rd line1927.14th line1521.45th line912.96th line912.97th line811.48th line and beyond1014.3HP-based regimens Chemotherapy + HP5477.1Endocrine therapy + HP57.1HP alone912.9Other22.9 Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [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 P4-13-20.

Hepatic Metastases is Associated with Poor Efficacy of Erlotinib as 2nd/3rd Line Therapy in Patients with Lung Adenocarcinoma.

BackgroundHepatocyte growth factor (HGF)-mediated mesenchymal-to-epithelial transition factor (MET) gene amplification is a common mechanism for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). MET gene amplification has also been associated with hepatic metastases in patients with lung cancer. The aim of this study was to investigate whether hepatic metastases are associated with decreased efficacy of erlotinib in patients with adenocarcinoma.Material/MethodsA cohort of 329 patients with stage IV lung adenocarcinoma, known EGFR mutation status, and who received treatment with erlotinib in the 2nd or 3rd line setting were enrolled into this study over a period of 4 years between January 2011 and January 2015. The cohort was stratified based on the presence or absence of hepatic metastases and the efficacy of erlotinib was defined based on disease control rate (DCR) and progression-free survival (PFS).ResultsHepatic metastases were present in 220 of the 329 enrolled lung adenocarcinoma patients. EGFR-activating mutations (exon 19 deletion or an exon 21 L858R mutation) were identified in 113 (34.3%) patients. The DCR was significantly lower in the hepatic metastases group than in patients without hepatic metastases (39.5% vs. 51.4% P=0.045). In patients with hepatic metastases, median PFS was 2.3 months in the EGFR mutation-positive group versus 1.4 months in the EGFR mutation-negative group (95% CI 1.3–3.3 vs. 1.3–1.5; P=0.055). Of note, erlotinib therapy in patients with hepatic metastases was complicated by elevated alanine transaminase (ALT) levels.ConclusionsHepatic metastasis in patients with lung adenocarcinoma predicts poor response to erlotinib as a 2nd/3rd line therapy. Combination therapy, for example with MET-TKI, may be a good choice for patients with liver metastases with poor prognosis.