2nd Line Tx Research Articles

On-treatment (tx) dynamic circulating tumor DNA changes (∆ctDNA) associated with progression-free survival (PFS) and overall survival (OS) of patients (pts) with HR+/HER2− advanced breast cancer (ABC) in MONALEESA-3 (ML-3).

1012 Background: In ML-3, ribociclib (RIB) demonstrated a significant PFS/OS benefit over placebo (PBO) in pts with HR+/HER2− ABC. We report associations of on-tx ∆ctDNA with OS/PFS and tumor size and of ctDNA detectability with radiological progression. Methods: Pts were randomized 2:1 to RIB or PBO + fulvestrant as 1st- or 2nd-line tx. ctDNA levels were measured by NGS at cycle 1 day 1 (C1D1), C4D1, C8D1, and every 8 cycles until end of tx. Analyses included: Wilcoxon rank sum text to compare ∆ctDNA from C1D1 to C4D1; Kaplan-Meier method to visualize relationship of ctDNA with PFS/OS; Cox proportional hazards model for associations of ctDNA and tumor metrics (objective response rate, best % change, % change at 1st tumor evaluation); Fisher’s exact test to compare ctDNA detectability between arms; and ∆ctDNA across time points to assess lead time between ctDNA level-based and radiological progression. Results: Overall, 534/726 (73.6%) pts had paired C1/C4 measurements. Rates of detectable (+) and undetectable (−) ctDNA at C1 and C4 were: C1+/C4+, 33.0%; C1+/C4−, 34.5%; C1−/C4−, 27.5%; and C1−/C4+, 5.1%. RIB vs PBO had a larger % decrease in ctDNA level from C1 to C4 (P=0.003). Pts with better best overall response also had larger ctDNA decreases from C1 to C4 (P<0.0001). On-tx ∆ctDNA from C1 to C4 correlated with PFS/OS (P<0.0001; Table). C1-/C4-, C1+/C4-, and C1+/C4+ strongly correlated with PFS within response categories (PR, SD, NCRNPD). C1-to-C4 % ∆ctDNA was only moderately correlated with tumor size change (best % change, r=0.41; change at 1st evaluation, r=0.32; both P<0.001). Univariate/multivariate analyses showed significant correlations between ctDNA metrics (% change, detection pattern at C4D1) and PFS/OS. ctDNA detection and % change generally remained significantly associated with PFS/OS even after adjusting for change in tumor size. In a longitudinal analysis of pts who cleared ctDNA at C4D1 (C4–), the median lead time between ctDNA progression and radiological progression was 8.2 mo (IQR 4.5–15.6). Conclusions: On-tx ∆ctDNA from C1 to C4 was correlated with PFS/OS even after adjusting for tumor size changes, suggesting that ctDNA and tumor dynamics capture distinct aspects of tumor tx responses. Decreases in ctDNA were greater with RIB vs PBO, mirroring ML-3 efficacy readouts but at a much earlier timepoint. This longitudinal analysis of ctDNA in ML-3 suggests that detecting ∆ctDNA is a sensitive way to monitor progression and may be a potential surrogate for efficacy in HR+/HER2− ABC. Clinical trial information: NCT02422615 . [Table: see text]

Analysis of therapy attrition and changes in outcomes over time for patients (pts) with advanced urothelial cancer (aUC) treated at an academic center.

590 Background: Despite recent advances in treatment (Tx) options for pts with aUC, real world data suggest that <50% of pts starting Tx receive 2nd line Tx and <15% receive 3rd line Tx. We hypothesized that aUC pts treated at an academic center would have lower Tx attrition rates which would translate into improved outcomes for pts treated more recently. Methods: We identified pts with aUC treated since 2011 and analyzed pts who received systemic Tx for metastatic disease, including baseline characteristics, Tx lines and outcomes. Date of 1/1/2019 for Tx start was used to divide pts into earlier vs later Tx groups. Overall survival (OS) from Tx start was assessed using Kaplan Meier Method in pts who started Tx >1 year before censor date of 12/31/2022 for survival. Chi-square test and Wilcoxon rank sum test were used to compare proportions and numerical data, respectively. Results: Among 360 pts with aUC, 237 received 1st line Tx from 09/2011-08/2022. Of 237 pts, 133 (56%) received 2nd line Tx, 61 (26%) 3rd line Tx, 30 (13%) 4th line Tx, and 10 (4%) > 4 Tx. Pts with Tx in the later group (start after 1/2019) had higher ORR with 1st and 2nd line Tx (Table) and more NGS testing (87% vs 54%, p<0.001) relative to earlier group. With median follow-up of 29.5 mos, median OS was 24.2 mos (95% CI: 17.4 – 29.7) for all pts. Pts in the later group (Tx started 1/2019-12/2021, n=94) had improved mOS relative to the 134 pts in the earlier group (30.6 vs 17.4 mos, p=0.02) despite similar number of average Tx lines (2.4 vs 2.5). Conclusions: During a decade when significant changes occurred in the aUC Tx landscape, pts treated at an academic center had lower Tx attrition rates than those described in real world settings during a similar timeframe. Notably, pts who started Tx after 1/2019 had improved OS relative to pts who started Tx earlier, despite similar number of average Tx lines. This finding may be driven by higher ORR to 1st and 2nd Tx lines in pts treated more recently. Validation in other academic centers and larger cohorts is needed. [Table: see text]

Abstract PD18-11: Dose-Expansion Study of Trastuzumab Deruxtecan as Monotherapy or Combined With Pertuzumab in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer in DESTINY-Breast07 (DB-07)

Abstract Background: In trials of HER2+ metastatic breast cancer (mBC), trastuzumab deruxtecan (T-DXd) monotherapy showed durable efficacy (DESTINY-Breast01) and significantly prolonged progression-free survival vs trastuzumab emtansine (DESTINY-Breast03). T-DXd is approved in the US for patients with HER2+ unresectable/mBC who received ≥1 prior anti-HER2–based treatment (tx) in the metastatic or neo-/adjuvant setting and recommended for approval in the EU as 2nd-line tx. Preclinical data suggest that T-DXd used in combination with other anticancer tx may lead to improved efficacy. The purpose of DB-07 is to assess the safety and efficacy of T-DXd alone or with other anticancer tx for patients with HER2+ mBC. Here we report preliminary data from the DB-07 dose-expansion phase for T-DXd monotherapy and T-DXd + pertuzumab (P) as 1st-line (1L) tx in mBC. Methods: DB-07 (NCT04538742) is an ongoing, phase 1b/2, 2-part (part 1: dose finding; part 2: dose expansion), modular, open-label trial of T-DXd alone or with other anticancer tx in patients with HER2+ mBC. In part 2, patients in module (mod) 0 received T-DXd 5.4 mg/kg every 3 weeks (Q3W) and in mod 2, T-DXd 5.4 mg/kg + P 420 mg Q3W (loading dose: 840 mg), the recommended phase 2 dose. Patients in these mods must be mBC tx naive. For part 2, the primary objective is to assess safety and tolerability. A secondary objective is to assess the objective response rate (ORR) per local investigators by Response Evaluation Criteria In Solid Tumors v1.1. We report results for patients randomized before Oct 13, 2021 to mods 0 and 2 of part 2 (data cutoff [DCO]: Mar 4, 2022); recruitment is ongoing. Based on the distinct mechanism of action of T-DXd and P, we conducted preclinical studies with the drugs in HER2-overexpressing cell lines to elucidate their potential synergies. To assess the effects on T-DXd internalization, live cell imaging was performed using pH-dependent fluorescently labeled T-DXd. To assess the effects on HER2 signaling, total and p-HER2 levels and downstream substrates were evaluated by immunoblot. Results: 23 patients were enrolled in the T-DXd monotherapy mod; 20 (87.0%) were receiving tx and 3 (13.0%) discontinued tx (withdrawal by patient, n=2; adverse event [AE], n=1) by DCO. 22 patients were enrolled in the T-DXd + P mod; 20 (90.9%) were receiving tx and 2 (9.1%) discontinued tx (AE, n=1; disease progression, n=1) by DCO. All patients experienced AEs (Table); 1 patient in each mod died. The unconfirmed ORR (80% CI) with T-DXd monotherapy and T-DXd + P was 82.6% (68.2%-92.2%) and 77.3% (61.9%-88.5%), respectively; updated data will be presented. Preclinical studies showed that T-DXd was more rapidly and effectively internalized in combination with P than when administered alone. Immunoblotting of cell lysates showed a greater reduction in total HER2 and HER2 signaling in response to combination tx than with T-DXd or P alone. Discussion: In summary, 1L T-DXd monotherapy and T-DXd + P safety profiles and antitumor activity were consistent with those previously reported for T-DXd. Mature data in these mods are awaited, and other T-DXd combinations are being investigated in additional mods. Preclinical studies showed the potential for P to induce greater internalization of T-DXd and inhibition of HER2-driven signaling. These results support investigation of T-DXd in larger ongoing trials (eg, NCT04784715). Table 1: Summary of treatment duration and safety data Citation Format: Erika Hamilton, Komal Jhaveri, Sherene Loi, Carey Anders, Peter Schmid, Konstantin Penkov, Elena Artamonova, Lyudmila Zhukova, Daniil L. Stroyakovsky, Dinesh Chandra Doval, Rafael Villanueva, Flavia Michelini, Sarat Chandarlapaty, Matt Wilson, Sarice R. Boston, Adam Konpa, Shoubhik Mondal, Fabrice Andre. Dose-Expansion Study of Trastuzumab Deruxtecan as Monotherapy or Combined With Pertuzumab in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer in DESTINY-Breast07 (DB-07) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-11.

P-152 The impact of 2nd-line treatment after 1st-line gemcitabine plus nab-paclitaxel in advanced pancreatic cancer patients

Three main phase III randomized studies investigated the role of 2nd-line tx in advanced pancreatic cancer (APC) patients (pts). The PANCREOX study failed to demonstrate a survival advantage of mFOLFOX vs 5FU/LV. Conversely, the CONKO-003 and NAPOLI-1 trials, demonstrated a significant survival improvement from the combination regimen OFF and 5FU+Nal-IRI, respectively, in comparison to 5FU/LV alone. Recently, final OS analysis from NAPOLI-1 demonstrated an association of specific characteristics (ECOG PS, age, Ca 19.9 baseline level, neutrophil-to-lymphocyte ratio and no liver metastases (m)) with OS > 1 year.

The impact of 2nd-line treatment (tx) after 1st-line Gemcitabine plus Nab-paclitaxel (GemNab) in advanced pancreatic cancer (APC) patients (pts).

e16759 Background: Three main phase III randomized studies investigated the role of 2nd-line tx in APC pts. The PANCREOX study failed to demonstrate a survival advantage of mFOLFOX vs 5FU/LV. Conversely, the CONKO-003 and NAPOLI-1 trials, demonstrated a significant survival improvement from the combination regimen OFF and 5FU+Nal-IRI, respectively, in comparison to 5FU/LV alone. Recently, final OS analysis from NAPOLI-1 demonstrated an association of specific characteristics (ECOG PS, age, Ca 19.9 baseline level, neutrophil-to-lymphocyte ratio and no liver metastases (m)) with OS > 1 year. The main limit of all these studies was due to the period they were carried out: no pts received 1st-line GemNab. Hence, we retrospectively analysed an homogeneous population of APC treated with 1st-line GemNab at our Institution, investigating the impact of 2nd-line tx. Methods: APC pts receiving a 2nd-line tx after 1st-line GemNab were included in the analysis. The following variables were collected: gender; age ( > vs ≤ 55 years and ≥ vs < 70 years ); baseline ECOG PS (0-1 vs 2-3); Ca 19.9 baseline level (≥ vs < 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); number of m sites (1 vs > 1); m sites (liver, peritoneum, lung, nodes); RECIST response and ETS during 1-line GemNab. Univariate and multivariate analyses for PFS and OS were performed. Results: Out of 167 APC pts progressed to 1st-line GemNab, 93 (56%) pts received a 2nd-line tx, specifically 58 pts received an oxa-based regimen, 11 FOLFIRINOX, 8 FOLFIRI and 16 pts received other tx. Median 2nd-line PFS and OS were 3.3 and 5.6 months, respectively. Out of 87 pts evaluable for response, 7 pts achieved a partial response and 27 a stable disease, with a RR and a disease control rate (DCR) of 8% and 39%, respectively. Pts with baseline ECOG PS 0-1 had a significant better outcome in comparison to pts with PS 3-4 (PFS 4.2 vs 1.2 months, p < 0.0001; OS 7.2 vs 2.6 months, p = 0.0001). This significant association with survival parameters and ECOG PS was confirmed at the multivariate analysis. Conclusions: Despite the limited number of pts evaluated and the restrospective nature of our analysis, our results are in line with previous evidences, confirming the importance of a 2nd-line combination tx, when feasible, as well in an homogeneous population of APC pts treated with 1st-line GemNab. On the basis of our results, ECOG PS may be considered a prognostic factor and the choice of 2nd-line tx should be guided in primis by the baseline general conditions of APC pts.

Sequential treatment with pazopanib followed by nivolumab in patients with renal cell carcinoma: Updated interim results of the non-interventional study PAZOREAL.

e17075 Background: Real-world evidence is urgently needed to monitor the translation of new treatment approaches into routine clinical practice as well as to improve cancer treatment and survivorship care. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness, tolerability, safety, and quality of life (QoL) in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) treated with 1st-line pazopanib (PAZO) followed by 2nd-line nivolumab (NIVO). The primary variable was time on drug (TD) in the respective treatment (Tx) lines. Other endpoints include overall survival (OS), safety and QoL evaluated by EQ-5D-5L. Results: Between December 2015 and September 2017, 414 pts were enrolled and 388 pts started first-line PAZO Tx, 136 pts subsequently received NIVO as second-line Tx. At time of data-cut (30 Sep 2019) median TD was 6.5 months (95%CI 5.7-7.6) for 1st-line PAZO and 4.6 months (95%CI 3.3-6.0) for 2nd-line NIVO. 9.0% of 1st-line PAZO pts and 5.9% of 2nd-line NIVO pts achieved a complete response and disease control rate was 58.0% (95% CI 53.0-62.8) and 44.9% (95% CI 36.8-53.2) for PAZO or NIVO, respectively. Median OS was 32.6 months (95% CI 28.0-38.9) for all pts, 32.6 months (95%CI 28.2-NA) for pts with 2nd-line NIVO and 32.3 months (95%CI 18.8-NA) for pts with other 2nd-line Tx. The most commonly reported treatment emergent AEs were diarrhea (37.2%), nausea (21.7%) and fatigue (19.1%) for PAZO Tx and diarrhea (8.8%), peripheral edema (5.9%) and dyspnea, fatigue, nausea, rash, vomiting (5.1% each) for NIVO. 66 pts (17.1%) discontinued PAZO and 7 pts (5.1%) discontinued NIVO due to related TEAEs. During 1st-line PAZO Tx, mean EQ-5D-5L utility scores initially decreased slightly by time, returned to baseline level and remained stable afterwards. During 2nd-line NIVO Tx the utility scores initially increased by time and remained stable thereafter. Similar tendencies were reported for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Conclusions: The interim results of the PAZOREAL study confirm favorable clinical trial outcomes, the good benefit-risk profile and the sustained QoL in pts with mRCC in a real-world setting. The sequential treatment with PAZO followed by NIVO is effective and well tolerated. Clinical trial information: NIS-Nr.: 6687.

A retrospective study evaluating clinical and molecular predictors of duration of response (DoR) to immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC).

e21581 Background: ICI with/without chemotherapy has become the standard of care for the treatment of advanced NSCLC. Little is known about the clinical and molecular predictors of DoR to these agents. We previously reported clinical predictors of DoR to ICI in NSCLC patients (pts). Here we report the correlation of molecular alterations with DoR and clinical/molecular characteristics of super responders (DoR ≥ 2yr) to ICI. Methods: A retrospective chart review of pts with advanced NSCLC treated with ICI based therapy between 2015-2018 at Karmanos Cancer Institute was conducted. Clinical, tumor, and molecular characteristics data were collected. DoR was grouped into: < / = 6 weeks, > 6weeks-6months, > 6mo-1yr, > 1yr, and super responders. Results: Of 147 pts, 68% had adenocarcinoma, 61% received prior radiation, 21% had brain metastasis (mets), 26% developed irAEs, 33% were on statin, 27% were on aspirin, 83% were current or former smokers, 55% had right sided primary tumor, ICI was 1st line treatment (tx) in 20% and 2nd line tx in 52%. Overall median DoR was 168 days (95% CI, 132-231 days). Pts with right sided primary tumors and those who received ICI as 1st line tx had longer DoR (p = 0.012 and p = 0.017; respectively). Other aforementioned covariates, including brain mets, had no significant relationship with DoR. Molecular profile (MP) of 592 genes was available for 57 (38.8%) pts. PD-L1 ≥50%, CDKN2A and NOTCH1 mutations were associated with statistically significant longer DoR. Mutations/alterations in EGFR, ALK, ROS1, MET, RET, HER2, KRAS, STK11 and TP53 did not appears to have an impact on the DoR, although some of the analysis was limited because of very small number of pts. Of the 10 super responders, majority had adenocarcinoma, received prior radiation and were current/former smokers. Two had brain mets. Most did not have concurrent use of anti-inflammatory agents (statin or ASA). Only 2 of the super responders had MP available with negative NOTCH1 and CDKN2A mutations. Conclusions: Receiving ICI as 1st line of therapy and having right sided primary tumors predicted longer DoR. Presence of brain mets did not adversely affect the DoR. Super responders were more likely to have adenocarcinoma, prior radiation therapy, and current/former smoking history. PD-L1 expression ≥ 50%, CDKN2A, and NOTCH1 were associated with longer DoR. Presence of actionable genomic alterations, STK11, KRAS and TP53 did not appear to impact DoR to ICI.

Radiomics risk score (RRS) on CT to predict survival and response to CDK 4/6 inhibitors in hormone receptor (HR) positive metastatic breast cancer (MBC).

e13041 Background: The addition of CDK 4/6 inhibitors (CDK) to endocrine therapy (ET) is the standard of care for HR+ MBC. Currently, no robust predictive markers for CDK inhibitors exist. We hypothesized that baseline imaging features on pre-treatment CT scans using machine learning could correctly identify responders to CDK. Methods: From a retrospective pt registry, 46 pts with HR+ MBC who received palbociclib (palbo) plus ET and had liver metastases were identified, and divided at random into equally sized training and testing cohorts. Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’ (65%), and those with progressive disease within 6 months were ‘non-responders’ (35%). The median age at diagnosis was 62. All pts were ER+ and 4% were HER2+. 65% pts received palbo as 1st or 2nd line tx. 503 radiomic texture features measuring subtle differences in lesion heterogeneity on a pixel level were extracted on pre-treatment CT within the first lesion measured for RECIST assessment. An elastic net Cox proportional hazards model was constructed within the training set to derive a Radiomics Risk Score (RRS), which was evaluated for association with prognosis and response within the testing set. A risk score threshold was chosen in the training set for stratifying patients into high and low risk groups. Results: The RRS consisted of 4 radiomic features indicating intratumoral heterogeneity to be associated with poor outcome. In the independent testing set (n = 23), RRS was continuously associated with survival (p = .0027) on multivariate analysis, along with age and RECIST response (Table). Categorical risk groups were similarly associated with survival in the testing set (p = .00491, HR = 4.03, CI = 0.6772). Median survival time in low and high risk groups were 2.33 and 0.673 years, respectively. When compared against RECIST response in the testing set, RRS was found to also be predictive of response with an ROC curve of 0.675. Conclusions: Radiomics analysis was able to predict response and survival in HR+ MBC pts prior to initiation of treatment with CDK. [Table: see text]

Expectations of overall survival for patients with metastatic pancreatic cancer (mPC).

e16788 Background: Pancreatic cancer is the 4th leading cause of cancer-related death in the U.S. Metastatic pancreatic cancer has typically had a poor prognosis. However, the use of combination chemotherapy with novel agents have improved outcomes. First line therapy with either FOLFIRINOX (2011) or gemcitabine (gem)/nab-paclitaxel (2013) improved response rates (RR), progression-free survival (PFS) and OS versus (vs) gem alone. In 2015, second-line therapy with nanoliposomal irinotecan and fluorouracil (5FU) also improved RR, PFS, and OS vs 5FU. Since 2017, several newer agents have been approved for targeted patient populations – pembrolizumab for MSI-H/dMMR tumors, larotrectinib and entrectinib for NTRK gene fusion positive pts, and olaparib for germline BRCA-mutated pts. As more treatment (Tx) options become available, pts are more likely to receive Tx in later lines. A population-based study found that of mPC pts who completed 1st-line (1L) chemotherapy prior to December 31, 2014, 49% went on to receive 2nd-line (2L) Tx and 17% received 3rd-line (3L) Tx6. Methods: Prescribing patterns of 569 U.S.-based oncologists were studied using a validated, proprietary, case-based market research tool (Challenging Cases). Data were acquired using blinded, audience-response iPad technology at 8 live events during 2018-2019. Results: Estimate of mPC patients treated with 2L and 3L Tx in 2019 Estimates for mPC pts treated with 2L therapy rose from 2018 to 2019, with 46% treating > 60% of mPC patients with 2L in 2018 compared to 54% in 2019. Oncologists estimated median survivals to be 7.4 months (mos) from the regimens they prescribe in 1L, 4.3 mos in 2L, and 2.3 mos in 3L. Conclusions: With the addition of new and more effective treatments for mPC, more patients are treated in the 2L and 3L settings. However, oncologists may underestimate the survival expectation with novel agents or regimens, particularly in later lines of therapy. [Table: see text]

Enhanced efficacy of anti-VEGFR2/taxane therapy after progression on immune checkpoint inhibition (ICI) in patients (pts) with metastatic gastroesophageal adenocarcinoma (mGEA).

362 Background: Most pts with mGEA do not respond to ICI or ramucirumab/paclitaxel (RAM/TAX). Emerging data suggest that ICI may potentiate subsequent therapy (Tx). In KN059 we unexpectedly observed durable responses in 2 pts on RAM/TAX after ICI (PMID 29674442). We examined if ICI impacts efficacy of subsequent RAM/TAX in a larger cohort and explored alterations in the tumor microenvironment. Methods: All pts with mGEA at Mayo Clinic (MN, AZ, FL) who received RAM/TAX (2014-19) were included. We compared best objective response rate (ORR: complete [CR] or partial response [PR]) per RECIST1.1 and overall survival (OS) in pts who received RAM/TAX with (Group A) vs without (Group B) immediately preceding PD-1 blockade. Chi square and multivariate logistic and Cox regression were used. We adjusted for total lines of Tx received and the line of Tx in which RAM/TAX was given, to control for potential differences in the biology of heavily treated pts or those receiving RAM/TAX as 2nd vs 3rd line Tx. We also adjusted for age and ECOG PS. Results: In total 87 pts met inclusion criteria. In the 19 pts (Group A) who received RAM/TAX (usually as 3rd line Tx) after progression on ICI, there was a 77% relative risk reduction of death after initiation of RAM/TAX compared to the 68 pts (Group B) who received RAM/TAX (usually as 2nd line) without preceding ICI (median OS 15.0 vs 7.6 mo; HR 0.23; P < .001). The ORR was also significantly higher (58% vs 18%; P < .001) including the CR rate (16% vs 1%; P = .006). Two CRs in Group A are ongoing (10 - 34 mo). Of note, 95% of Group A pts did not respond to ICI, and all had irRECIST progression on ICI. Immunofluorescent analysis from a responder showed 65-fold reduction (post vs pre-Tx) in intratumoral density of immunosuppressive FOXP3+ Tregs, with preserved density of antitumor CD8+ T cells. Conclusions: Higher than expected efficacy was observed on RAM/TAX when immediately preceded by ICI, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This serial immunotherapy combination may be a novel option for pts with primary resistance to ICI and will be tested prospectively in a new randomized phase 2 trial (NCT04069273).

570P - Treatments (tx) after progression to first-line FOLFOXIRI + bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and TRIBE-2 studies by GONO

BackgroundFOLFOXIRI + bev is regarded as a valuable option in the first-line tx of mCRC pts. A possible concern for the adoption is the feasibility and efficacy of tx after progression, and especially the reintroduction of the same agents used upfront. The aim of the study was to evaluate the efficacy of tx after progression among pts treated with first-line FOLFOXIRI + bev in the phase III TRIBE (NCT00719797) and TRIBE2 (NCT02339116) studies. The impact of the oxaliplatin and irinotecan free interval (OIFI), defined as the time from the last administration of oxaliplatin and irinotecan to disease progression, on the efficacy of tx after progression was also investigated. MethodsData about tx received after progression including 2ndPFS (i.e. the time from 2nd line tx start to disease progression or death) were collected. The efficacy of tx after progression according to the duration of the OIFI was explored. A cut-off value of 4 months was adopted. ResultsOut of 586 pts treated with upfront FOLFOXIRI + bev, 520 progressed. Among 409 (79%) pts who received a tx after progression, 168 (41%) received FOLFOXIRI ± bev (Group A) and 241 (59%) received other tx (Group B), including FOLFOX or FOLFIRI ± bev or other agents not used in first line in 124 and 117 cases, respectively. Anti-EGFR moAbs were administered in 68 cases.Pts in Group A experienced significantly longer 2nd PFS than pts in Group B (median 2nd PFS: 6.1 vs 4.2, HR 0.76, 95%CI 0.62-0.94; p=0.012). Pts with an OIFI ≥ 4 mos (n=279) had longer 2nd PFS than those with an OIFI < 4 mos (n=130) independently of the second-line tx (6.1 vs 3.7 mos: HR 0.54, 95%CI 0.42-0.69; p<0.001). In the subgroup of pts with an OIFI ≥ 4 mos FOLFOXIRI ± bev (n=125) was associated with longer 2nd PFS compared to other tx (n=154) (7.2 vs 5.5 mos; HR 0.75, 95% CI 0.58-0.97; p=0.029). Conversely, in pts with an OIFI < 4 mos no significant difference was shown between Group A (n=43) and B (n=87) (4.4 vs 3.2; HR 0.94, 95%CI 0.65-1.36; p=0.75). ConclusionsTx after progression to first-line FOLFOXIRI + bev were feasible. Pts with longer OIFI showed better 2nd PFS and seemed to derive more benefit from the reintroduction of the triplet. Clinical trial identificationTRIBE NCT00719797 TRIBE2 NCT02339116. Legal entity responsible for the studyG.O.N.O.: Gruppo Oncologico Nord Ovest. FundingHas not received any funding. DisclosureS. Lonardi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Servier. D. Santini: Advisory / Consultancy: Amgen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Eisai; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck. A. Falcone: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier. C. Cremolini: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Servier. All other authors have declared no conflicts of interest.

Treatments (tx) after progression to first-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and MOMA studies by GONO group.

3542 Background: FOLFOXIRI plus bev is regarded by international guidelines as a valuable option in the first-line tx of mCRC pts. One of the major concerns for the adoption of this regimen is the potential limitation of subsequent therapeutic options. The aim of the present analysis was to focus on treatments received after progression in TRIBE (NCT00719797) and MOMA (NCTNCT02271464) studies. Methods: We collected data of tx received after progression and their outcome in terms of 2ndPFS (time from 2nd line tx start to disease progression or death) and OS II (time from 2nd line tx start to death). For pts in which the same drugs used in first-line were totally or partially reintroduced, the chemotherapy-free interval (CFI, time from the last administration of irinotecan or oxaliplatin during first-line to disease progression) was calculated. Results: Out of 482 pts treated with upfront FOLFOXIRI plus bev, 429 progressed. 303 (70.6%) pts received a 2nd line tx: 93 FOLFOXIRI +/- bev (Group A), 119 FOLFOX/XELOX or FOLFIRI +/- bev (Group B) and 91 other tx (Group C), including an anti-EGFR moAb in 60 cases. No difference was observed among the three groups in terms of 2ndPFS (median 2nd PFS Group A: 5.6 vs Group B: 4.4 vs Group C: 3.9 mos; p = 0.60) or OS II (median OS II Group A: 14.9 vs Group B: 13.8 vs Group C: 11.7 mos; p = 0.49). In the subgroup of pts with a CFI &lt; 6 mos, Group A (n = 52) reported longer 2ndPFS compared to both Group B (n = 58) (median 2ndPFS 5.3 vs 3.0 mos; HR: 0.61,95%CI 0.41-0.89; p = 0.009) and Group C (n = 58) (5.3 vs 3.2 mos; HR: 0.71, 95%CI 0.48-1.05; p = 0.07). Consistent results were achieved in OS II (Group A vs Group B; median OS 13.6 vs 10.8 mos; HR: 0.65, 95%CI 0.42-1.00; p = 0.053; Group A vs Group C 13.6 vs 8.9 mos; HR: 0.60, 95%CI 0.39-0.93; p = 0.002). In the subgroup of pts with a CFI ≥ 6 mos, no significant difference was shown between Group A (n = 41) and Group B (n = 61) or C (n = 33). Conclusions: Tx after progression to first-line FOLFOXIRI plus bev are feasible and show expected efficacy results. The reintroduction of the triplet plus bev seems more effective than doublets plus bev or other tx when a more aggressive disease biology is suggested (CFI &lt; 6 mos).

Serial measurements of myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (CI).

e16005 Background: MDSC are a heterogeneous population of immunosuppressive cells with potentially predictive implications in UC pts receiving CI. We hypothesized that MDSC populations may change after CI exposure. Methods: Serial peripheral blood samples were collected from mUC pts treated with CI. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. The Wilcoxon signed rank and rank sum tests were used to assess changes in MDSC populations while on CI. Results: 17 pts treated with CI (9 atezolizumab [A], 8 pembrolizumab [P]) had ≥ 2 MDSC samples for analysis. Median age at diagnosis was 71 (46-81), 12 men, 29% never smokers; 53% / 29% / 18% ECOG PS 0/1/2 and 59% visceral metastasis at the time of 1st sample collection. 10 pts received CI as 1st line therapy (Tx) in metastatic setting; 7 pts received chemotherapy as 1st-line Tx for mUC (6 platinum-based, 1 docetaxel) and CI as 2nd-line Tx. In 16 pts with samples before 1stdose, there was a relative decrease (median 36.3%, range -59.7 to +21.2) in PBMC % I-MDSCs between 1st and 2nd samples (p=0.06). Interestingly, PBMC %M-MDSC and %I-MDSC tended to increase compared to baseline in pts treated with P, while they tended to decrease in pts treated with A (Table). Conclusions: In this cohort of pts with mUC treated with CIs,MDSC changes differed based on CI (anti-PDL1 or anti-PD1). Further study in larger cohort with various prior Tx lines and longer follow up as well as correlations with Tx response, toxicity and outcomes are ongoing. [Table: see text]

Retrospective review of subsequent treatments (tx) for esophagogastric adenocarcinomas (EGA) refractory to FOLFOX.

123 Background: FOLFOX is a preferred 1st-line tx for advanced EGA. We sought to characterize outcomes on subsequent tx and to see if MSK-IMPACT, a 410-gene next generation sequencing (NGS) platform, increases tx options. Methods: We retrospectively identified patients (pts) with advanced, Her2-negative EGA treated with 1st-line FOLFOX between Jan 2012 to Dec 2014. Clinicopathologic, tx and outcome data were analyzed. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis was used to compare OS and response status. Results: 185 pts were identified. The majority were Caucasian (82%), male (76%), ECOG PS 1 (67%), with poorly differentiated histology (72%) and de novo metastatic disease (84%). Median age was 64 years. The disease-control rate (DCR, partial response + stable disease) of FOLFOX was 80% [95%CI: 74%-85%]; 19% were FOLFOX primary refractory (FR). Median time-to-progression (TTP) on FOLFOX was 7 and 2 months (mo) for FOLFOX sensitive (FS) and FR pts, respectively. There was a higher proportion of females (26% vs. 14%, P = 0.18), gastric (43% vs. 23%, P = 0.051) and moderately differentiated tumors (26% vs. 12%, p = 0.113) in the FS vs. FR group. Six mo survival from the landmark time of 2 mo after initiation of FOLFOX was 83% [95%CI: 76%-89%], and 38% [95%CI: 20%-56%] for FS and FR pts, respectively (p &lt; 0.01). A similar proportion of FS and FR pts received 2nd-line tx (65% vs. 69%). The DCR was similar in both groups (31% vs 29%). 2nd-line tx included: irinotecan- (51%) and taxane-based regimens (32%) or a clinical trial (CT) (13%). The median TTP on 2nd-line tx was similar in FS and FR groups (2.5 vs 2 mo). Ramucirumab was given in 14% of 2nd line regimens. 3rd-line chemo use was similar in both groups (37% vs 31%) but the DCR was lower in FR patients (18% vs. 9%). 51 pts had IMPACT; 1 pt (2%) enrolled onto a genotyped-matched CT. 14 pts received immunotherapy; 1 FS Pt has ongoing complete response 1+ year. Conclusions: Surprisingly, FS and FR pts derive similar, marginal benefit from 2nd-line tx, emphasizing the appropriateness of CT options in this setting. NGS rarely expanded tx options. Updated and in-depth NGS data will be presented.

Molecular biomarkers as predictors of patient survival in pancreatic adenocarcinoma (PDA): An analysis of the Know Your Tumor initiative (KYT).

278 Background: Recent studies have expanded our knowledge of the genomic landscape of PDA. While critical and in some cases, potentially actionable alterations are being identified, limited outcomes data have thus far made it difficult to validate the relevance of these observations. Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have facilitated commercial tumor molecular profiling for over 400 PDA pts since 2014 through KYT, and have developed a database of molecular and clinical information useful for data mining of biomarker-survival correlations. The survival significance of biomarkers was assessed using standard statistical methodology including Kaplan-Meier analysis and Cox proportional hazard models. Results: Linked molecular and outcomes data were available for 360 pts, of which 173 had treatment (tx) information available. Pathogenic mutations from targeted NGS, protein expression from IHC, and protein phosphorylation from RPPA were screened for correlations with overall survival (OS) and progression-free survival (PFS) independent of tx received. As shown in the table, mutations in 3 genes were associated with a better OS; while mutations in 8 genes were associated with poorer OS. Only two mutations were correlated with PFS in 1st or 2nd-line tx ( BRCA2 and KDM6A, worse PFS). Positive expression of 7 proteins, including TS, TOP1, and RRM1, were associated with reduced OS but were not correlated with PFS. High levels of phospho-ribosomal protein S6 were associated with both poor OS (HR=10.3, p=0.001) and poor PFS (HR=9.6, p=0.006). Conclusions: Multiple biomarkers had significant correlations with OS in PDA, while fewer were correlated with PFS. Growth of this registry database will further validate tx-specific predictive biomarkers for use in pts with multi-omic profiling data. [Table: see text]

Healthcare Utilization (HRU) and Costs Among Multiple Myeloma (MM) Patients (Pts) Receiving Second or Subsequent Line Treatment (Tx) with Carfilzomib (CAR) or Pomalidomide (POM)

Background A recent retrospective study compared healthcare outcomes and costs in pts with MM receiving CAR or POM using health insurance claims data and reported that CAR pts had higher healthcare costs than POM pts (Parikh ASCO 2016). The results of this analysis have not been confirmed by other investigators.Objective To compare HRU and costs among pts receiving monotherapy with CARor POM +/-dexamethasone (dex) as 2nd or subsequent Tx for MM in the US using a health insurance claims database.Methods This was a retrospective observational study using the MarketScan® database. Pts were adults with MM (ICD-9-CM code 203.0) who initiated MM Tx, including CAR, POM, bortezomib, lenalidomide, thalidomide, and other chemotherapies (CT) for MM, between Jan 1, ’06 and Dec 31, ’14. Pts were excluded for (1) Receipt of a MM Tx before the first MM diagnosis date (Dx date) (2) enrollment gap during the 180-days before Dx date, or between Dx date and the first day on Tx, or the 30 days after Tx initiation, or (3) age <18 y at Tx initiation.Medical/pharmacy claims for MM Tx including CT were tracked for each pt since Tx initiation. After initiation of a first treatment, subsequent lines of therapy (LOT) were identified based on evidence of a new Tx after 90 days since LOT initiation, or >90-day gap in Tx. For each pt with ≥1 CAR or POM LOT, the first LOT with CAR or POM was defined as the index LOT. The date of initiation of this LOT was defined as index date. Pts with CAR or POM as 1st line Tx or in combination with other CT (excluding dex) or with stem cell transplant (SCT) during the index LOT were excluded. Monthly HRU and costs during the index LOT (total, on Tx, off Tx) were compared for pts receiving monotherapy (+/- dex) with CAR vs. POM using inverse probability of treatment weights (IPTW) to obtain average treatment effect (ATE) estimates controlling for measured baseline covariates. IPTWs were based on propensity scores for receipt of CAR estimated by logistic regression with LOT, age, sex, region, plan type, Charlson index, comorbidities, pre-index healthcare cost, and receipt of prior SCT as covariates.Results We identified 114 CAR and 144 POM pts. CAR pts were more likely to receive index Tx in 2nd vs. subsequent LOT, initiate LOT after 2013, be male, and have chronic renal disease, anemia, and diabetes. POM pts were more likely to have prior SCT, chronic pain, and coronary heart disease. Based on examination of standardized differences, IPTW samples were well balanced in baseline characteristics. IPTW adjusted mean monthly total healthcare costs were $19,776 with POM vs. $17,321 with CAR (difference=-$2,455, p=0.52) (Table). Consistent with its mode of administration, the adjusted mean monthly numbers of visits and costs of Tx administration were greater for CAR. The adjusted mean monthly number prescriptions (Rx) were greater for POM vs. CAR. Otherwise, there were no statistically significant differences between groups in adjusted mean monthly total HRU and costs.Conclusions IPTW-adjustedmonthlyHRU and costs do not vary significantly for pts receiving monotherapy with CAR or POM +/- dex for 2nd or subsequent line Tx for MM. To avoid potential bias, treatment comparisons using real world evidence require consideration of patient characteristics that may influence treatment choices and outcomes. [Display omitted] DisclosuresPanjabi:Amgen, Inc.: Employment, Equity Ownership. Hagiwara:Amgen, Inc.: Research Funding. Delea:Amgen, Inc.: Research Funding.

Real world treatment patterns of previously treated advanced gastric and gastroesophageal junction adenocarcinoma (GC) in Mexico.

143 Background: Little evidence is available on the management of patients (pts) with advanced GC after 1st-line treatment (tx). Until recently, no licensed therapies for 2nd-line tx were available. This study presents real-world data on pts characteristics, tx patterns, and resource utilization for these pts in Mexico. Methods: Data from medical charts was collected from 3 centers (tertiary-level). Eligible pts were ≥ 18 years old, diagnosed Jan 2007 - Jan 2015 with advanced or metastatic GC, had received 1st-line fluoropyrimidine+platinum, had ≥ 3 months of follow-up after 1st-line discontinuation, and had not participated in a clinical trial. Data were summarized using descriptive statistics. Results: Data from 180 charts was collected; the majority from the Mexican Institute of Social Security (IMSS) (167; 92.8%). Pts' mean age was 57.2 (±12.4) years and 56.7% were male. ECOG performance status (PS) during 1st-line tx was 78.3% PS = 1, 17.2% PS = 2, 0% PS = 0. A total of 16 unique 1st-line regimes were identified, of which EOX (32.2%), XELOX (23.3%), and ECF (14.4%) were the most frequent. The most common reasons for discontinuation were completion of planned regimen (27.2%), toxicity (27.2%) and disease progression (16.7%). A total of 151 (83.9%) pts received 2nd-line chemotherapy. Of these, 54.3% were PS = 1 and 33.1% PS = 2. A total of 19 regimes were identified; with the most frequent being capecitabine (34.4%), docetaxel (16.6%), and XELOX (13.9%). Among pts who received 2nd-line chemotherapy, 50 (33.1%) received 3rd-line chemotherapy. Resource use for patients receiving 2nd-line chemotherapy was: pain interventions (7.3%), nutritional support (1.3%), radiotherapy (13.9%), transfusions (10.6%), inpatient care (15.2%), emergency room visits (2.0%) and outpatient visits (other than scheduled follow-up) (3.3%). Conclusions: This study shows considerable variation in chemotherapy regime in both 1st- and 2nd-line therapy of pts with advanced GC. Understanding GC tx patterns in Mexico will help address unmet needs. Limitations: Pts who did not receive 2nd-line tx are likely underrepresented because these pts are typically managed at local clinics and not tertiary hospitals.

Prescribing preferences (PPrefs) of US-based medical oncologists (MOs) for 1st salvage therapy (Tx) after response to 1st-line crizotinib (CRZ) in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC).

e19137 Background: Crizotinib is standard 1st line Tx for ALK-positive NSCLC. 2nd line Tx after progression on CRZ is less well defined. Shaw, et al (N Engl J Med 2013; 368:2385-2394) showed that A...

841P - Metastatic Renal Cell Carcinoma (Mrcc) Treated with Targeted Therapies (Tt) in the Community Setting: an Italian Survey on 1238 Pts

ABSTRACT Aim: This survey verified reproducibility in the real world of the survival data reported in the literature. Methods: This study reviewed individual data of 1238 pts treated with TT from mid 2007 to December 2012 in 35 Italian Institutions. Results: Median age was 66 yrs (range 24-91). Histology was clear cell (CC) (84%), with sarcomatoid component (7%), others (9%); nephrectomy was performed in 88% of the pts and 36.5% of the pts presented with ≥3 metastatic sites. PS (ECOG) was 0 in 53%, 1 in 34%, ≥2 in 9%, ne in 4% of the pts. Median OS (mOS) was 24 mo. Sunitinib (su) was the 1stline (ln) therapy (tx) in 964 pts (78%), sorafenib (so) in 152 (12%), temsirolimus (tem) in 51 (4%), others in 71 (5%). Response rate to 1st ln tx was: CR 4%, PR 31%, SD 30%, PD 28%, ne 7%. In 918 evaluable pts, MSKCC risk score was poor (10%), intermediate (46%) and good (18%). Dose reduction was required in 46%; 39% of the pts had a duration of 1st ln tx 6 mo, no tx interruption, no dose reduction were statistically related to execution of 2nd line tx. Cox multivariate analysis showed that execution of 2nd line tx, no dose reduction, type of drug, 1st ln duration >6 mo, CC histology, no tx interruption, MSKCC risk score, PS, type of response were statistically related to OS. mOS (all p Nephrectomy vs not 28 / 6.5 Metastatic sites ≤2 vs ≥3 31 / 18 PS 0 vs 1 vs ≥2 38.5 /18.6 / 6 CR vs PR vs SD vs PD 62.5 /39 / 29 / 7.8 Poor vs intermediate vs good MSKCC risk score 6.4 / 26 /46 Dose reduction: yes vs not 19.8 / 33.6 1st ln duration 6 mo 9.1 / 36.5 Conclusions: This large survey: i) confirmed survival data for the individual drugs ii) identified predictive and prognostic factors iii) showed similar OS between the principal sequences of tx. Disclosure: All authors have declared no conflicts of interest.

Treatment (tx) patterns and drug (Rx) costs for patients (pts) with metastatic renal cell carcinoma (mRCC) in the United States.

457 Background: The tx paradigm for mRCC has rapidly morphed from cytokine-based and cytotoxic tx to targeted therapy (TT). Five oral (O) and two intravenous (IV) TTs are approved for mRCC. No consensus exists on the sequence of TT use. This study aimed to examine the evolution of 1st through 3rd line tx patterns since 2004 and their associated costs. Methods: LifeLink Health Plan Claims Database (October 1, 2003-March 31, 2011), a commercial claims database, was used to create a cohort of age ≥ 18 yo, mRCC pts with at least 12 months of continuous enrollment. We examined tx patterns and sequences by year. When evaluating cost, we limited analysis to pts &lt;65 yo because the database does not have information on claims paid by Medicare. We described pt characteristics and tx patterns over time and applied a nonparametric bootstrapping method to compare costs. Results: 1,561 mRCC pts met the inclusion criteria with 71% men and a mean age of 62 yo (SD=11); 39% were from the South; 57% had a modified Charlson comorbidity score of zero. In 2010: 9 unique Rx regimens were used for 1st line tx, 8 for 2nd, 8 for 3rd; most common 1st/2nd/3rd line tx was sunitinib (44%)/temsirolimus (24%)/everolimus=sunitinib (26%); most common sequence was VEGF-&gt;mTOR for the 1st switch and VEGF-&gt;VEGF-&gt;VEGF for 2nd switch. From 2004 to 2011, 1st line cytotoxic tx decreased from 47% to 6%, IFN-α from 47% to 3%, bevacizumab from 33% to 9%. Over time, more pts were able to go from 1st to 2nd line tx (p=0.01) and 2nd to 3rd line tx (p=0.025). Median time to switch (TTS) from 1st to 2nd line was 175 days (SD 103) with a longer TTS if started on O vs. IV tx (188 vs. 143 days) (p&lt;0.001). For 959 pts &lt;65 yo, stratifying by whether the 1st line tx was O or IV, mean total 1st-yr tx cost/pt was $130,962 (IV) vs. $121,676 (O) (P=0.18) and total 1st-yr Rx cost was $36,636 (IV) vs. $54,596 (O) (p&lt;0.001). Also, costs increased by the number of switches, from $108,428 for no switch to $190,976 for &gt; 1 switch. Conclusions: The results support a drastic shift in the tx of mRCC with wide heterogeneity in tx patterns, reflecting a lack of clear guidelines. Over the years, more pts are able to receive more lines of tx, TTS was longer with initial O tx, but 1st-yr Rx costs were lower with initial IV tx.