Tx Line Research Articles

Leukocyte immunoglobulin-like receptor (LILRB2)-targeted JTX-8064 plus the anti-PD1 inhibitor JTX-4014 (pimivalimab) in immune-checkpoint inhibitor (ICl) pretreated patients (pts) with advanced or metastatic renal cell cancer (mRCC): Results from the multi-stage phase 1-2 INNATE trial.

4531 Background: Disease progression following treatment of mRCC pts with ICl-based therapy (tx) is nearly universal, warranting evaluation of novel immunotherapeutic approaches. LILRB2 is an immune checkpoint molecule expressed primarily in cells of myeloid origin (e.g., monocytes/macrophages). Inhibition of LILRB2 reprograms macrophages from an immunosuppressive (M2) to an immunostimulatory (M1) phenotype. JTX-8064 is a humanized monoclonal antibody that binds to LILRB2, blocking its interaction with MHC1 molecules. Preclinical studies suggest that JTX-8064 can overcome anti-PD(L)1 resistance mechanisms. Here we report the results of an expansion cohort of previously-treated mRCC pts in INNATE, a multi-stage phase 1-2 trial of JTX-8064 in combination with anti-PD1 agents in solid tumors. Methods: Pts with pathologically-confirmed clear cell mRCC progressing on or after anti-PD(L)1 tx in the most recent prior line, acceptable end-organ function, and ECOG PS 0-1 were treated with JTX-8064 700 mg and JTX-4014 500 mg IV q3 weeks. Primary endpoint was overall response rate (ORR); secondary endpoints were safety, disease control rate (DCR), progression-free survival (PFS), & overall survival (OS). A Simon 2-stage design (n=10+19) was employed where ORR >= 20% was deemed to be of further interest versus null hypothesis of ORR <= 5%, with alpha=0.05. Results: 31 pts were enrolled, with median age of 64 years (range 38-85); 84% males; 16% Hispanic; 93% White; 45% PS=0; 71% one prior tx line. Of 28 pts evaluable for response, 1 CR, 1 PR, 14 SD (6 SD>= 6 months), and 11 PD were seen for an ORR of 7% & DCR of 54%.Median PFS was 4 months (95%CI: 2, 6.8); 12-month OS was 75% (95%CI: 55,88). Tx-related adverse events (AE) of all grades were reported in 11 pts (45%), most commonly fatigue (16%) & diarrhea (10%). Only 4 protocol-related G3-4 AEs were reported: thrombocytopenia (G4); diplopia, diarrhea, & bradycardia (all G3). Three on-study deaths (hypotension; cardiorespiratory arrest; & unknown) were deemed unrelated to protocol tx. Conclusions: While ORR did not meet the protocol-defined efficacy target, evidence of anti tumor activity was seen in ICI pre-treated mRCC pts with combination JTC-8064 + JTX-4014. Treatment was reasonably well-tolerated. Identification & evaluation of clinical and molecular phenotypes most likely to benefit from LILRB2-targeted therapies are warranted. Clinical trial information: NCT04669899 .

Abstract PO1-13-02: Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study

Abstract Introduction: Combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) + endocrine therapy (ET) is recommended as first- or second-line treatment (1L or 2L Tx) for hormone receptor-positive, human epidermal growth factor receptor-2-negative metastatic breast cancer (HR+/HER2− mBC). In this study, we assessed cancer-specific genetic alterations in circulating tumor DNA (ctDNA) and tissues in abemaciclib-treated patients with HR+/HER2− mBC in Japan. Methods: MONSTAR-SCREEN is a multicenter study and part of a nation-wide cancer genome screening project for patients with advanced solid tumors (SCRUM Japan). Regardless of the Tx line, the current analysis included abemaciclib-treated patients with HR+/HER2− mBC (N=97). Data were collected between Jan 2020 and Dec 2021. Blood samples collected at ≤21 days before abemaciclib initiation (baseline; n=77) and at disease progression or Tx discontinuation (paired post-Tx; n=33) were tested with the FoundationOne® Liquid Companion Diagnostic panel. Additionally, archival or fresh tissue biopsy samples (n=79) were tested with the FoundationOne® Companion Diagnostic panel. Patient characteristics, baseline genetic alterations, neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]), and alterations at clinical progression were reported. Results: The total population (N=97) included patients with next generation sequencing ctDNA and/or tissue data. All were female with median age of 57 years (interquartile range 50, 67). Bone, either alone or with other sites, was the most common metastatic site (61%). 78% of patients received abemaciclib in the first or second line of Tx (LoT). Fulvestrant with or without gonadotropin-releasing hormone (55%), letrozole (24%), and anastrozole (11%) were the most common concomitant drugs. Among patients with baseline ctDNA data (n=77), 30% and 21% had received prior ET and prior chemotherapy, respectively. In baseline ctDNA samples, PIK3CA (37%) and TP53 (28%) alterations were detected most frequently across all LoT; while ESR1 (16%), GATA3 (11%), and FGF3/4/19 (9%) were more frequently detected in samples from later LoT. The frequency of ESR1 alterations (p< 0.01), shedding rate, and maximum VAF (both p< 0.05) were significantly higher in prior ET recipients than those who did not receive prior ET. Frequency of post-Tx ESR1 alterations numerically decreased from baseline in patients on fulvestrant (23% to 18%) and numerically increased in patients on aromatase inhibitors (27% to 45%). Other genes showed either a numeric increase or similar alteration frequency between the baseline and post-tx. Newly acquired post-Tx alterations were detected in FGF3/4/19 (18%); PIK3CA, TP53, and RB1 (all 15%) and ESR1 (12%). The table shows PIK3CA and ESR1 alterations detected at baseline and post-Tx. In the tissue samples (n=79), TP53 (32% vs 20%) and ESR1 (14% vs 7%) alterations were numerically more frequent in metastatic versus primary lesions. Other gene alteration frequencies were similar. Conclusion: PIK3CA alterations were the most frequently detected genetic alterations in both pre- and post- abemaciclib Tx patients with HR+/HER2− mBC. Patients with prior ET had more frequent ESR1 alterations and higher neoplastic burden. Evidence from this study provides insight into the ctDNA dynamics and potential resistance mechanisms in patients with HR+/HER2− mBC. PIK3CA and ESR1 alterations detected in circulating tumor DNA at baseline and post abemaciclib treatment Citation Format: Masaya Hattori, Victoria Serelli-Lee, Yoichi Naito, Takashi Yamanaka, Hiroyuki Yasojima, Rikiya Nakamura, Takao Fujisawa, Mitsuho Imai, Yoshiaki Nakamura, Hideaki Bando, Tsutomu Kawaguchi, Takayuki Yoshino, Hiroji Iwata. Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-02.

Epcoritamab + R2 regimen and responses in high-risk follicular lymphoma, regardless of POD24 status.

7506 Background: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment (tx) with chemoimmunotherapy (CIT), POD24, occurs in around 20% of patients (pts) and strongly predicts poor outcomes. There is no standard tx approach for high-risk, relapsed or refractory (R/R) FL (high-risk subgroups in Table). Novel options are needed to improve efficacy in pts with high unmet need. Epcoritamab, a subcutaneous (SC) T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al, Lancet 2021) and shows promise combined with standards of care. Here we present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab with rituximab + lenalidomide (R2). Methods: Pts with R/R CD20+ FL received epcoritamab SC + R2 for 12 cycles (Cs; 28 d each). Epcoritamab was dosed QW in C1–3, Q2W in C4–9, and Q4W in C≥10 (2a) or QW in C1–2 and Q4W in C≥3 (2b) for ≤2 y. Results: As of Oct 31, 2022, 109 R/R FL pts had received epcoritamab 48 mg + R2 in 2a and 2b. Median age was 65 y, 56% of pts had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior tx. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on tx. The most common tx-emergent AEs were: CRS and neutropenia, 48% each; injection-site reactions, 38%; and fatigue, 33%. CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose on C1D15; all resolved and none led to discontinuation. ICANS occurred in 2 pts (G1, G2) and resolved. In 101 efficacy-evaluable pts, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Notably, pts achieved higher ORR/CMR rates with epcoritamab + R2 vs their immediate prior tx line (ORR, 97% vs 85%; CMR, 86% vs 60%). Estimated 6-mo progression-free survival was 93%. In second-line (2L) pts with POD24, ORR/CMR rates were 95%/90% (additional high-risk subgroup data in Table). Additional data with longer follow-up will be presented. Conclusions: Epcoritamab + R2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in pts with high-risk disease, suggesting epcoritamab SC may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066). Clinical trial information: NCT04663347 . [Table: see text]

Analysis and optimization design of control signal line parasitic effects on streaking phenomenon in CMOS image sensor

This paper presents an optimization scheme for charge transfer control signal (TX) line to suppress the streaking phenomenon in CMOS image sensor (CIS) with FD-Shared. The influence of the streaking phenomenon in the image is evaluated by the increment of dark pixels. By building the mathematical model of streaking phenomenon, the relationship between the size of TX line and the increment of dark pixels is revealed. The simulation results show that for a 6.144 cm (H) × 8.192 cm (V) pixel array under 110 nm CMOS process, when the width of the TX line is 0.4 μm, the increment of dark pixels is the smallest. The minimum increment is 0.1709 DN at 0 dB and 2.7080DN at 24 dB. The increment is linearly amplified by the readout circuit gain. In the chip design, the streaking phenomenon can be alleviated according to the model analysis and optimization scheme given in the paper.

Real-world treatment (tx) patterns, cost, and overall survival (OS) by line of therapy among patients (pt) with mantle cell lymphoma (MCL): A SEER-Medicare (SM) analysis.

19 Background: MCL is an aggressive form of non-Hodgkin’s lymphoma with an incidence of 1 in 200,000 in the United States. Limited evidence exists on real-world tx utilization, costs, and survival outcomes associated with MCL among older pts in the US. This study examined tx patterns and quantified cost and OS in first- (1L), second- (2L), and third-line (3L) settings in SM pts with MCL. Methods: This retrospective cohort study included older pts (age ≥ 66 yrs) with MCL, identified using a SM-linked database from 01/01/2013 to 12/31/2017, and followed for 2 yrs. Pts were eligible if they had ≥ 1L MCL tx with ≥ 6 months (mo) of continuous enrollment before and after MCL diagnosis. Pts with other primary malignancies or stem cell transplantation (SCT) ≤ 6 mo before first diagnosis of MCL were excluded. A tx regimen was defined as combination of all agents ≤ 35 days of tx initiation; rituximab (R) monotherapy initiated ≤ 7 mo after R-containing regimen was considered maintenance. For each tx line, all-cause and MCL-specific health care resource utilization (HCRU) and costs were calculated per pt per year (PPPY) and adjusted to 2021 US dollars. Kaplan‒Meier method for survival analysis was used to estimate OS in 1L, 2L, and 3L settings. Results: This study included 559 pts with newly diagnosed MCL: median (range) age, 75 (66‒94) yrs; male, 59.7%; mean Charlson Comorbidity Index, 1.44; stage IV (45.3%), and poor performance status (12.2%); subsequently, 305 (54.6%) received 2L and 153 (27.4%) received 3L tx. The most common regimens were bendamustine + R (51.7%) in 1L and ibrutinib in 2L (17%) and 3L (15.7%). For 1L, 2L, and 3L, 6.3%, 14.8%, and 8.5% of pts received radiation therapy, and 0.4%, 5.1%, and 8.6% received SCT, respectively. Median time to next treatment from start of previous line was 245, 127, and 222 days for 1L to 2L, 2L to 3L, and 3L to 4L, respectively. Mean (SD) all-cause total (medical + drug) costs were $169,210 ($174,904), $209,092 ($254,229), and $185,718 ($220,495) PPPY. The median OS from MCL diagnosis until end of follow-up was 47.2 mo (95% CI, 40.9‒53.7). The 12-mo survival was 81.1% (95% CI, 77.5%‒84.9%), 71.4% (95% CI, 65.5%‒77.9%), and 69.9% (95% CI, 61.8%‒79.1%) for 1L, 2L, and 3L, respectively. Conclusions: The study results report substantial costs associated with the use of standard care therapies among older pts with MCL. New treatments are needed to improve clinical outcomes, and reduce HCRU and overall healthcare costs in MCL.

MajesTEC-3: Randomized, phase 3 study of teclistamab plus daratumumab versus investigator’s choice of daratumumab, pomalidomide, and dexamethasone or daratumumab, bortezomib, and dexamethasone in patients with relapsed/refractory multiple myeloma.

TPS8072 Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) after prior therapy with a proteasome inhibitor (PI) and lenalidomide are challenging to treat. Daratumumab in combination with pomalidomide and dexamethasone (DPd) or bortezomib and dexamethasone (DVd) are approved for pts with RRMM; however, disease control could be further improved. There is an unmet need for new therapeutic options with different modes of action. Teclistamab (tec; JNJ-64007957) is a B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. In the phase 1, MajesTEC-1 study (NCT03145181), tec monotherapy was well-tolerated and showed encouraging efficacy in heavily pretreated pts with RRMM. The combination of tec and daratumumab (tec-dara) in the phase 1b TRIMM-2 study (NCT04108195) was also well-tolerated with promising efficacy. MajesTEC-3 (NCT05083169) is a multicenter, open-label, randomized phase 3 study that will compare the efficacy of tec-dara versus investigator’s choice of DPd or DVd in pts with RRMM. Methods: Pts (≥18 years old) must have documented MM per International Myeloma Working Group (IMWG) criteria; measurable disease; Eastern Cooperative Oncology Group performance status 0–2; received 1–3 prior treatment (tx) lines, including a PI and lenalidomide (pts with 1 prior tx line must be lenalidomide-refractory); with progressive disease on or after their last tx (or within 60 days of completing lenalidomide). Pts who received prior BCMA-directed tx or who are refractory to an anti-CD38 monoclonal antibody will be excluded. ̃560 pts will be randomized 1:1 to receive 28-day cycles of tec-dara or investigator’s choice of DPd or DVd (stratified by investigator’s choice of DPd or DVd, ISS stage, and number of lines of prior tx). Step-up doses of tec will be given prior to the first tx dose. Dara, DPd and DVd will be administered per approved schedules. Pts will be treated until disease progression, death, intolerable toxicity, withdrawal of consent or end of study, whichever occurs first. Response will be assessed per 2016 IMWG criteria. The primary endpoint will be progression-free survival (PFS). Secondary endpoints include overall response rate, complete response or better, MRD negativity, PFS on next-line tx (PFS2), overall survival, and incidence and severity of AEs. Adverse events (AEs) will be graded by Common Terminology Criteria for AEs v5.0, except for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which will be graded by American Society for Transplantation and Cellular Therapy guidelines. The study opened in October 2021 and enrollment is ongoing. Clinical trial information: NCT05083169.

Abstract P1-18-37: Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world

Abstract Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 & 6i) provide significant benefit for patients (pts) with HR+, HER2- MBC, however, clinical questions remain regarding the optimal sequence (seq) of treatments (tx). Prior analyses of real world (rw) abemaciclib indicate up to 50% of pts have had prior palbociclib or ribociclib for MBC and published studies regarding seq and non-seq tx outcomes have had limited sample sizes. To our knowledge, the current study represents the largest rw analysis of CDK4 & 6i tx seq to date. Methods: US electronic medical records were retrospectively analyzed from the ConcertAI Oncology Dataset. Pts received abemaciclib and ≥ 1 other systemic tx line for HR+, HER2- MBC; the study period was 11/1995 (date of first MBC dx in dataset) to 10/2020 (end of follow-up). Tx sequences were identified and grouped to enable outcomes analyses. Data for 4 select groups (grp) are presented: grp 1 (1L CDK4 & 6i to 2L CDK4 & 6i), grp 2 (1L CDK4 & 6i to 2L non-CDK4 & 6i), grp 3 (2L CDK4 & 6i to 3L CDK4 & 6i), grp 4 (2L CDK4 & 6i to 3L non- CDK4 & 6i). Progression-free survival (PFS) from regimen start date to disease progression or death was analyzed by line using Kaplan-Meier method; pts were censored on the start date of the subsequent tx or end of follow-up if a progression event was not reported. Pts were characterized as having primary or secondary endocrine resistance per ESMO guidelines, if applicable. Pt characteristics at initiation of 1st CDK4 & 6i and median PFS are summarized descriptively. Results: Of 690pts, the majority were white (n=555, 80%), had a median age of 61yrs (range 26-86) and were treated in community oncology practices (80%) in southern US (47%). Most pt characteristics between grp 1 vs grp 2 were not statistically different except for pts participating in clinical trials [grp 1 (n=3; 2%) vs grp 2 (n=12; 13%)]. Pts in grp 4 were younger than grp 3, with a median age of 60 and 67yrs, respectively (p<0.05). In the overall cohort, the most prevalent tx seq grp was 1L CDK4 & 6i followed by 2L CDK4 & 6i (n=165). There was significant treatment regimen heterogeneity across all grps, with the most frequent being 1L palbociclib/AI followed by 2L abemaciclib/fulvestrant received by 26 (16%) pts. Abemaciclib was prevalent in 1L (n=92; 13%), 2L (n= 204; 30%), 3L (n=122; 18%), ≥4L (n=344; 50%). Pts receiving seq CDK4 & 6i experienced a substantial PFS benefit in the subsequent line (grp 1: 17mo; grp 3: 11mo), while pts in non-seq grps experienced a numerically lower PFS from the non-CDK4 & 6i tx in the subsequent line (grp 2: 8mo; grp 4: 8mo). Median PFS for each grp is described in Table 1. Results of cox proportional hazards models will be presented. Conclusions: Seq CDK4 & 6i appears to deliver substantial 2L PFS in pts who had a meaningful PFS on 1L CDK4 & 6i. These results appear consistent for pts receiving 3L CDK4 & 6i who had a meaningful PFS to 2L CDK4 & 6i. While most pts received 1L CDK4 & 6i to 2L CDK4 & 6i, there was marked tx heterogeneity across all seqs in this predominantly community oncology sample, reinforcing the continued lack of consensus on this topic. While these results are hypothesis generating, these data serve as further rationale for additional prospective and retrospective studies evaluating the potential utilization and outcomes of CDK4 & 6i, after progression on a previous CDK4 & 6i. Table 1.Grp 11L CDK4 & 6i to 2L CDK4 & 6i n=165Grp 21L CDK4 & 6ito 2L non-CDK4 & 6i n=94Grp 32L CDK4 & 6i to 3L CDK4 & 6i n=115Grp 42L CDK4 & 6i to 3L non-CDK4 & 6i n=121Line 1No. of Events/Pts78/16572/94Median (m)18.459.8095% CI[15.0, 23.2][6.4, 14.2]Line 2No. of Events/Pts55/16540/9455/11587/121Median (m)17.308.3917.308.2995% CI[9.8, 33.4][5.9, 10.5][12.1, 21.0][6.2, 9.9]Line 3No. of Events/Pts46/11557/121Median (m)11.227.8695% CI[6.8, 14.0][5.5, 11.3] Citation Format: Kevin M Kalinsky, Megan Kruse, Emily Nash Smyth, Claudia M Guimaraes, Santosh Gautam, Alnecia R Nisbett, Maxine D Fisher, Zhanglin Lin Cui, Lee Bowman. Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-37.

Treatment Patterns and Outcomes of Multiple Myeloma (MM) with Chromosome Translocation (11;14) in United States (US) Routine Clinical Practice

Treatment Patterns and Outcomes of Multiple Myeloma (MM) with Chromosome Translocation (11;14) in United States (US) Routine Clinical Practice

3rd-line anaplastic lymphoma kinase (ALK) inhibitors (ALKi) in advanced non-small cell lung cancer (aNSCLC): Real-world comparison to non-ALKi therapy.

e21685 Background: ALKi represent the standard 1st- and 2nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3rd-line setting is unclear. We retrospectively assessed the real-world impact of a 3rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts. Methods: Consecutive ALK+ aNSCLC pts were identified in the working databases of 7 Israeli oncology centers; pts receiving any systemic Tx beyond 2 different ALKi were selected for the comparative analysis. Pts whose immediate next Tx line (post-2nd-ALKi) was a 3rdALKi (Group (Gr) A) were compared to pts whose immediate next Tx line (post-2nd-ALKi) was non-ALKi Tx (Gr B), in terms of overall survival (OS) and time to next Tx line (TNT). Results: 158 consecutive ALK+ aNSCLC pts diagnosed in January 2011 - March 2019 were included, median follow up from diagnosis of aNSCLC was 41 months (mo) (IQR 8-45). Median OS from aNSCLC diagnosis was 56 mo (95% CI 36-66). Post-2nd-ALKi line was a 3rd ALKi for 23 pts (Gr A) and a non-ALKi Tx for 10 pts (Gr B). 7 of Gr B (70%) received ALKi as a later line Tx. Median OS after initiation of post-2nd-ALKi Tx was 27 mo (95% CI, 7-NA) for Gr A vs. 16 mo (95% CI, 7-NA) for Gr B; p-non-significant (NS) with or without adjustment for sex, age, brain metastases. TNT on post-2nd-ALKi Tx was 6 mo (95% CI, 2-27) for Gr A vs. 2.5 mo (95% CI, 0-NA) for Gr B; p-NS. Conclusions: Following progression on a 2ndALKi, OS and TNT were numerically higher for pts receiving a 3rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. [Table: see text]

Personalized ANtibodies for GastroEsophageal Adenocarcinoma (PANGEA): Primary efficacy analysis of the phase II platform trial (NCT02213289).

356 Background: 1-yr OS is ~40% for HER2- & ~55% for HER2+ advanced (aGEA). Targeted therapies (tx) have had limited benefit due to molecular heterogeneity. Methods: This phase 2a study of a personalized tx strategy (PTS) enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) lines: first line (1L) 5FU + oxaliplatin, 2L 5FU + irinotecan & 3L 5FU + docetaxel. Baseline biomarker profiling (BP) was mandated on primary & metastatic tumors (PT/MT) & progressive disease points (PD1, PD2). Assigned antibody (AN) was added to cx by a predefined prioritized tx algorithm (PTA) (Table) based on the MT BP. At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per PTA. The same was done at PD2. If AN was unavailable (MET/FGFR2), these pts were tx’d with cx alone (not ITT). The 10 endpt was 1-yr OS of the PTS. Assuming historical 50% 1-yr OS for all aGEA pts, 68 pts tx’d per protocol PTS provided 80% power to detect an HR=0.67, corresponding to a 1-yr OS rate of 63% (under exponential survival), using a 1-sided test at the 0.10 alpha level. 20 endpts: safety, feasibility, PT/MT BP discordance at baseline & over tx line, & OS/PFS/ORR by tx line & BP group. Results: Between 6/2015-5/2019, 80 consecutive pts enrolled at 3 sites: ECOG PS 0-2 40/33/7; Male 80%; median age 60, range 28-81, peritoneal disease 36%. AN assigned by PTA at 1L & 1-yr OS are shown (Table). PT/MT discordance was 37%. Of 68 pts treated by PTS ITT, the 1-yr OS was 69.4% (p<0.001). The mOS was 16.4m [95%CI 13.8-20.8]. Any grade >3 tox thru all 3 tx lines was seen in 32% of pts. 20 analyses will be presented. Conclusions: PANGEA was feasible & met its 10 efficacy objective with observed 1-yr OS of 69.4%, meriting a randomized study. Clinical trial information: NCT02213289 . U.S. National Institutes of Health.[Table: see text]

A Line-Array Technique for Wireless Power Transfer Toward a 100 $\mu$ m $\times100$ $\mu$ m Coil Antenna

Wireless power transfer (WPT) has grown rapidly in the past decade to power up devices such as radio frequency identification (RFID) tags, sensors, and medical implants. In recent years, miniaturization has become a new key requirement for some emerging applications such as the Internet of Things (IoT) and biomedical devices. Targeting at a miniaturized receiving (Rx) coil, conventional-inductive WPT (IWPT) has insufficient power transfer gain. The multi-coil transmitting (Tx) array techniques mainly aim at improving the misalignment tolerance, but the power gain (or efficiency) is significantly limited by the mutual coupling among the Tx elements. In this article, we propose a new Tx array structure formed by lines instead of coils. The line-array technique keeps the antimisalignment character of the conventional multi-coil arrays, while the power gain is enhanced in two ways: 1) the lossy adjacent sides are removed in the line array, and 2) the mutual coupling among the array elements is alleviated. To validate the proposed technique, we demonstrate a Ku-band WPT prototype, including a CMOS Rx rectenna and a printed circuit board (PCB) Tx line array. The rectenna is fabricated in a 65-nm CMOS technology, with a coil antenna measuring $100 \mu \text{m} \times 100 \mu \text{m}$ . At varying power transfer ranges, the power transfer gain and misalignment tolerance are measured for both the single-coil and line-array systems, respectively. In comparison to the conventional single-Tx-coil IWPT, the overall power gain can be improved by 17.3 dB at a typical power transfer range of 2.5 mm, while a 1-mm misalignment only reduces the gain by 1.3 dB.

356P - Use of trastuzumab emtansine (T-DM1; K) after pertuzumab + trastuzumab (PH) in patients with HER2-positive metastatic breast cancer (mBC): Challenges in assessing effectiveness of treatment sequencing in the real world (RW)

BackgroundIntroduction of PH (2012) and K (2013) in the US changed the standard-of-care for HER2-positive mBC. RW studies reported decreased K effectiveness in pts with PH pre-tx. We studied whether timing of PH and K availability in clinical practice could introduce selection bias (i.e. pts with K after PH in early yrs of availability may have to have had rapid progression during PH tx to be included in RW analyses). MethodsUsing de-identified data from the US-based Flatiron electronic health record-derived database, we selected pts diagnosed with mBC on/after 1 Jan 2011 and initiating K between 1 Feb 2013 and 31 Jul 2018. Primary analysis included all pts receiving K (any tx line). Subgroup analysis focused on pts with 2nd-line K tx after PH tx. Time from index date to next tx/death (TTNT) was used as a proxy for progression-free survival. ResultsPrimary cohort (N=533) demographics were generally consistent across yrs (2013–18); median age was 61 yrs; 89% had prior HER2-targeted tx; 23% had brain metastases (mets); 68% had visceral mets. In pts with (n=231) vs without (n=79) prior PH, median age was 61 vs 65 yrs, mean time from mBC diagnosis was 16 vs 18 months, 27% vs 20% had brain mets, 74% vs 58% had visceral mets. Additional findings are shown (Table). Prevalence of prior PH exposure almost doubled over the yrs. In 2nd-line K treated pts with prior PH, time from mBC to K increased over the yrs, paralleled by a numerical increase in median TTNT.Table356PTable201320142015201620172018Primary cohort (N=533)N517710810611774Prior PH, n (%)18 (35.3%)35 (45.5%)72 (66.7%)80 (75.5%)77 (65.8%)53 (71.6%)TTNT, median months (95% CI)6.8 (4.9–14.2)6.5 (4.2–9.2)7.6 (4.7–9.8)6.3 (5.1–8.4)8.4 (6.4–10.3)Data not yet mature% Censored13.7%10.4%9.3%17.0%36.8%Subgroup analysis (N=231)Pts with 2nd-line K use after PH, N132556515234mBC to K initiation in pts with 2nd-line K use after PH, mean months (SD)12.7 (6.9)13.1 (8.5)13.0 (8.0)16.0 (12.9)17.9 (12.5)18.6 (11.6)TTNT in pts with 2nd-line K use after PH, median months (95% CI)5.1 (3.0–7.5)7.2 (4.6–11.7)6.6 (4.5–8.4)10.3 (5.6–12.8)Data not yet mature% Censored7.9%8.9%15.7%40.4%CI, confidence internal; SD, standard deviation. ConclusionsPrevalence of PH pre-tx increased, yet K effectiveness remained consistent across yrs. With PH launched shortly before K, the initial pts receiving K were possibly selected due to shorter benefit from prior PH. This selection bias may explain reports of lower K effectiveness in pts with prior PH tx. This illustrates the challenges of assessing tx sequence effectiveness shortly after tx approval. Editorial acknowledgementWriting assistance was provided by Meredith Kalish, MD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), and funded by F. Hoffmann-La Roche Ltd. Legal entity responsible for the studyF. Hoffmann-La Roche Ltd. FundingF. Hoffmann-La Roche Ltd. DisclosureT. Sanglier: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Flores: Full / Part-time employment: Genesis Research. E. Flahavan: Shareholder / Stockholder / Stock options: Eli Lilly; Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. N. Lindegger: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche; Shareholder / Stockholder / Stock options: Novartis; Shareholder / Stockholder / Stock options: Idorsia; Shareholder / Stockholder / Stock options: J&J. F. Montemurro: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Ely Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

A health-related quality-of-life (HRQoL) analysis of pomalidomide + low-dose dexamethasone + daratumumab in relapsed refractory multiple myeloma (RRMM) after lenalidomide treatment.

8025 Background: Treatment (Tx) of RRMM is complex and requires evaluation of disease and patient (pt) factors to maximize efficacy and minimize toxicity. HRQoL has become an important aspect of MM Tx, as survival has improved with therapeutic advances. Results of the ongoing phase 2 MM-014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in RRMM pts after first- or second-line lenalidomide (LEN)-based Tx failure. Here we report the impact of this regimen on HRQoL. Methods: RRMM pts with 1 to 2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during or after their last Tx line received POM + LoDEX + DARA in 28-day cycles (MM-014 cohort B). HRQoL, an exploratory endpoint for cohort B, was assessed via EuroQol’s EQ-5D. Results: As of October 15, 2018, 108 pts were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ-5D completion rates for each cycle (1-6) were ≥ 88%. Mean change from baseline in the EQ-5D index and VAS health score was stable through 6 Tx cycles. At cycle 6, 28.8% and 39.0% of pts achieved minimum clinically important improvement in the EQ-5D index (≥ 0.1) and VAS health score (≥ 6), respectively. EQ-5D index values were stable, with a trend toward improvement in usual activities, pain/discomfort, and anxiety/depression (Table). Conclusions: In RRMM pts with early-line LEN Tx failure, HRQoL was maintained or trended toward improvement with POM + LoDEX + DARA, despite the combination of 3 drugs with distinct toxicities. These findings further support the earlier use of POM-based Tx in RRMM immediately after LEN failure. Clinical trial information: NCT01946477. [Table: see text]

Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): Primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial.

1038 Background: A contributor to ETR, phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation can result from mutations to PIK3CA; ~40% of pts with HR+, HER2– ABC exhibit tumors with this mutation. Use of the oral α-specific PI3K inhibitor ALP + FUL significantly improved progression-free survival (PFS) in pts with a PIK3CA mutation (HR 0.65; 95% CI, 0.50-0.85; P<0.001) in SOLAR-1, which included both ET sensitive (ETS) and ETR pts (Table). ETS pts were later excluded by a protocol amendment. ETR was further defined as primary (1R) or secondary (2R) per ESMO criteria in both 1L and 2L pts. This subgroup analysis evaluated pts with a PIK3CA mutation based on tx line and endocrine status. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP 300 mg QD or PBO Q28d + FUL 500 mg Q28d + C1d15 in men and postmenopausal women with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor. PFS was estimated by Kaplan-Meier method and median PFS (mPFS) presented by tx arm. A stratified Cox proportional hazards model estimated HR and 2-sided 95% CI. Results: Of 341 pts in the PIK3CA mutant cohort, 39 (11%) were ETS; 302 (89%) were ETR. mPFS in the ALP vs PBO arms was 22.1 vs 19.1 mo (HR 0.87; 95% CI, 0.35-2.17) for ETS pts and 9.4 vs 4.2 mo (HR 0.64; 95% CI, 0.48-0.84) for ETR pts. For ETR pts, mPFS for 1L (n=138) was 9.0 vs 4.7 mo (HR 0.69; 95% CI, 0.46-1.05) and for 2L (n=161) was 10.9 vs 3.7 mo (HR 0.61; 95% CI, 0.42-0.89). Conclusions: In SOLAR-1, mPFS was improved with ALP + FUL vs PBO + FUL across ETR pts in 1L and 2L. Representation of ETS pts was low in SOLAR-1, which included more ETR pts. Analysis of the PI3K pathway in ETS pts is warranted in future studies. Clinical trial information: NCT02437318. [Table: see text]

Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic urothelial cancer (mUC) receiving atezolizumab (atezo) monotherapy in United States clinical practice.

381 Background: Atezo (anti–PD-L1) was the first immune checkpoint inhibitor approved for mUC. Here, we describe pt characteristics, time on tx (TOT) and distribution of tx cycles for pts receiving atezo in clinical practice, to complement data from clinical trial setting. Methods: Pts diagnosed with mUC who initiated atezo monotherapy in the first-line (1L) or second-line and beyond (2L+; prior platinum tx) settings on or before Jun 30, 2017, were identified from the US-based Flatiron Health electronic health record–derived database. Tx data were analyzed through Mar 31, 2018. TOT was defined as time from first to last atezo administration, plus 1 cycle length. Median TOT was calculated by tx line using the Kaplan-Meier method. Tx cycles were calculated by the number of atezo doses received during TOT. Corresponding results from global atezo clinical trials are presented. Results: Real-world data (RWD) from 312 pts (n = 102, 1L; n = 210, 2L+) met the study selection criteria (Table). Median TOT was 3 and 3.5 months in the 1L and 2L+ settings, respectively, with 95% CIs overlapping with the trial TOT data. A median of 4 cycles (IQR, 2-7, 1L; 2-9, 2L+) was administered in both settings. Conclusions: This is the first study of RW atezo use in mUC. The TOT with atezo observed in a US RW setting and the clinical setting (IMvigor210/IMvigor211) was similar. [Table: see text]

Temperature-Robust Air-Gapless EE-Type Transformer Rails for Sliding Doors

In this paper, a sliding EE transformer (SEET) rail, which has a strong and independent magnetic coupling to the gap variation between the transmitter (Tx) line and receiver (Rx) coil for powering the sliding door, is newly proposed. In the SEET rail, the Tx line and the Rx coil share a single EE ferrite core, while the winding window of the ferrite core is considered as the gap variation. In the proposed structure, the magnetic coupling can be maintained as strong and constant even though the ferrite core moves along the door rail when the sliding door is closed or opened. Through detailed coil designs based on electric and magnetic circuit analyses, design constraints on voltage, output power, flux density, and zero voltage switching are proposed with a closed-form solution of output voltage and theoretical maximum output power. The SEET rail is successfully designed to provide a maximum load power of 200 W for the sliding door within an ambient temperature range from −40 to 125 °C by following design constraints. Moreover, optimal design parameters such as number of turns, air-gap, and ferrite thickness are provided, which maximize power transfer efficiency of the SEET rail while maintaining its performance in the temperature range. The proof-of-concept prototype shows a strong magnetic coupling, κ = 0.76 at 20 °C and the variation of the magnetizing inductance with respect to the temperature variation was measured as 13.8%. The maximum power transfer efficiency excluding the regulator at a nominal load power of 100 W was 85%, and the efficiency at the maximum load power of 200 W was measured as 82% with a 3%P variation by the temperature variation.

Real-world data on overall survival (OS) impact of anti-EGFR sequence in patients (pts) with microsatellite stable (MSS) all-RAS and BRAFV600E wild-type metastatic (met) colorectal cancer (CRC).

3551Background: Pts with MSS all-RAS and BRAFV600E wild-type met CRC are more likely to respond to anti-EGFR drugs, irrespective of treatment (tx) line, particularly if left-sided primaries (prim)....

Anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma.

60 Background: Gastroesophageal cancer (GEC) is a global health problem. Multiple phase III anti-EGFR trials of unselected metastatic GEC patients (pts) were negative, yet subset analyses suggested potential benefit in pts with EGFR amplification (amp). We sought to quantify the incidence of EGFR amp in metastatic/recurrent GEC pts compared to the locally advanced TCGA rate, treat them with EGFR antagonists, quantify response/duration, and assess for mechanisms of action and resistance (MOA, MOR). Methods: 106 stage IV GEC pts in any therapy (tx) line (L) were prospectively screened for EGFR amp between 9/1/14-8/31/16 at a single site using tumor next generation sequencing (NGS). EGFR amp samples were then assessed by FISH, immunohistochemistry (IHC) and mass spectroscopy (MS) to confirm. Pts received 1L ABT-806 (1/4) or 2L+ cetux (3/4) monoclonal anti-EGFR antibodies, in combination with chemotherapy if 1L or 2L (2/4), or as monotherapy for 3L+ (2/4). Pts were followed for response (ORR) and disease control (DCR). Pre and post-treatment NGS, serial ctDNA, and EGFR/PD-L1 FISH/IHC/MS were obtained to monitor for MOA and MOR to tx. Results: Six (5.7%) pts harbored EGFR amp tumors with copies/cell ranging 54-167. Four eligible pts received >1 dose of tx with monoclonal anti-EGFR therapy: 1 FOLFOX-ABT-806 (1L), 1 FOLFIRI-cetux (2L), and 2 cetux alone (3L, 4L); ORR was 100% (4/4) by RECIST, respectively (-70%, -65%, -77%, -43%). All 3 cetux treated pts developed classic rash, which disappeared when/if progression (2/3). The 4-month DCR was 75% (3/4). No pts showed PD-L1 staining pre/post therapy. Upon progression, the 2L pt acquired de novo PTEN exon 6 deletion after 10 months, while basal NRAS mutated and HER2 amp ctDNA clones had expanded in the 4L pt after 4 months of monotherapy. Conclusions: EGFR amp incidence was similar to TCGA. Despite large negative trials with EGFR antagonists for GEC, EGFR amp predicted benefit (100%) from anti-EGFR tx, including monotherapy in 50%, albeit until various resistance mechanisms emerged, including HER2, RAS, and PTEN/AKT pathway activation. No PD-L1 expression was observed pre/post treatment, consistent with our previous data showing that EGFR-amplified cases trend towards a ‘non-T cell-inflamed’ phenotype. Clinical trial information: NCT01416714 / NCT02213289.

Clinical and molecular determinants of treatment benefit with phase I trials in patients (pts) with advanced pancreatic cancer (PC).

409 Background: PC is the 4th leading cause of cancer-related death, with limited efficacy of systemic treatment (tx) beyond first-line chemotherapy (chemo). We aimed to assess the potential benefit of phase 1 trials in this setting. Methods: From 2011 to 2016, 49 pts were enrolled in 54 phase 1 trials at our institution. Clinical and molecular data were retrospectively extracted from medical records. Time to progression (TTP) was calculated from time of tx start to discontinuation due to progressive disease, and clinical benefit rate (CBr) was defined as partial response or stable disease > 4 months. Results: Median age was 58 (41-75), 69% were male, 60% had metastases in liver. Most pts received gemcitabine-based regimens (47%) or Folforinox (32%) as first-line tx (median TTP of 5.63 months [CI 95% 4.0-8.1]). Median tx line of Phase 1 trial was 3 (range 2-5). Regimens included chemo or immunotherapies (chemo-imm group) in 16 cases (12 and 4, respectively), small molecule inhibitor (SMI) as single-agent in 19 cases (SMI.1 group), and SMI in combinations in 19 cases (SMI.2 group). In 17 cases, tx was matched to genomic profile; most frequent matches were PI3K + MEK SMI or RAF SMI ( KRAS mut in 7 pts), PI3K SMI ( PTEN loss/ PIK3CA mut in 3 pts) and PD1 blockade (PDL1 high in 4 pts). There were 3 (6%) partial responses (PI3K SMI unmatched, RAF SMI matched and anti-PD1 agent matched) and 12 (24%) disease stabilizations. Median TTP in phase 1 trial was 1.9 months [CI 95% 1.6-2.5], without significant differences if matched/unmatched agent (p = 0.5) or tx given as second-line/later regimen (p = 0.5). Median TTP was 2.7 months [CI95% 1.6-10.7] with chemo-imm (control arm), 2.0 months [CI95% 1.8-5.6] with SMI.2 (HR = 1.8, p = 0.13) and 1.4 months [CI95% 1.3-2.8] with SMI.1 (HR = 3.0, p = 0.004). This difference was maintained in a multivariable model (HR = 2.9, p = 0.005). CBr with chemo-imm (38%) or SMI.2 (21%) was higher as compared with SMI.1 (5%; p = 0.06). Conclusions: Selected PC pts are eligible to phase 1 trials and up to one-third derive substantial benefit from the intervention. In our experience, chemo-imm agents or targeted SMI given as combination regimens associate with longer TTP and CBr when compared with single-agent SMI.