We present microring-assisted Ge avalanche photodiodes (MRA-Ge APDs) fabricated on a 300-mm platform. The MRA-Ge APD exhibits an on-resonance responsivity of 0.82 A/W at −1.0 V. In addition, an avalanche gain of 7.5 is achieved at −6.1 V with the good uniformity across the 300-mm wafer. The MRA-Ge APD supports 56 Gbaud (NRZ and PAM4) operation.

Over the past decade, sub-wavelength diffractive optics has emerged as a promising field of research, offering attractive optical characteristics that allow for the manipulation of the amplitude and phase of incident light on flat surfaces. In particular, metalenses have shown strong potential to replace bulk refractive optical elements with ultra-thin planar platforms. In this study, we present a comparative analysis of wavefront aberration between sub-wavelength, nano-sized dielectric metalenses and commercial plano-convex (PCX) lenses at an infrared (IR) wavelength of 1,550 nm. We developed an off-axis interferometry system to observe the point-spread function (PSF) at the focal plane from phase-resolved interference patterns. The phase distribution across the wavefront was observed and calculated using Zernike polynomials. Additionally, we measured the focal spot size, modulation-transfer function (MTF), and Strehl ratio. Through this analysis, we found that the metalenses demonstrate diffraction-limited characteristics and are strongly competitive or even superior to the commercial PCX lenses in most metrics under the designed monochromatic wavelength.

BACKGROUND:Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS:Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS:In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS:In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Silicon (Si) photodiodes play a crucial role in complementary metal-oxide-semiconductor (CMOS) image sensors, particularly in visible cameras, and are increasingly in demand for infrared or short-wavelength (SWIR) cameras in modern autonomous vehicles operating under various weather conditions. However, the bandgap energy of 1.12 eV in Si limits its capability to detect light in the infrared range, only allowing visible light detection. In this study, we propose transparent, quantum-thickness, Schottky-junction photodiodes on Si for light detection from visible to SWIR wavelengths. We employ an atomically thin TiO2 interfacial layer between an n-type Si substrate and a nanometer-thick metallic layer, which is positioned beneath a transparent conductive oxide (TCO) layer, to create n-Si/TiO2/TiN/ITO multilayered Schottky-junction photodiodes. Without the typical p-n junction in Si, we observed photocurrents through interband transitions by incident photons in the wavelength range of 400 similar to 1,100 nm. Additionally, small but noticeable amounts of photocurrent were also measured by internal photoemission (IPE) via hot carrier generation even at the wavelength of 1,310 nm. The embedded TiO2 layer significantly reduced dark current by two orders of magnitude with little change in photocurrent or quantum efficiency. This can be attributed to the low conduction band offset of the TiO2 semiconductor, which contributes to a quantum tunneling barrier without changing the Schottky barrier height and disturbing the internal photoemission process.

Repotrectinib, a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI), has shown clinical activity and manageable safety in pts with ROS1+ NSCLC or NTRK+ locally advanced/metastatic solid tumors in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). This is the first report of repotrectinib efficacy by Blinded Independent Central Review (BICR), with 8.7 mo minimum follow-up in pts with TKI-naïve and -pretreated NTRK+ solid tumors, including NSCLC, and safety in all pts treated at the recommended phase 2 dose (RP2D). Pts with NTRK+ solid tumors were enrolled in TKI-naïve and -pretreated cohorts. RP2D was 160 mg QD for 14 d, then 160 mg BID. Phase 2 primary endpoint: confirmed objective response rate (cORR) by BICR. At data cutoff (19 Dec 2022), median follow-up was 17.8 mo (range, 8.7–64.6) in the TKI-naïve cohort (n = 40), and 20.1 mo (8.7–69.4) in the TKI-pretreated cohort (n = 48). The table shows efficacy in pts with NTRK+ solid tumors and subgroups of interest. NSCLC was the most common tumor (TKI-naïve, 52%; TKI-pretreated, 29%). In TKI-naïve NTRK+ NSCLC, cORR was 62% (95% CI, 38–82) and estimated 12-mo duration of response (DOR) and progression-free survival (PFS) was 92% (95% CI, 76–100) and 64% (43–86), respectively. In TKI-pretreated NTRK+ NSCLC, cORR was 42% (18–71) and estimated 12-mo DOR and PFS was 44% (1–88) and 23% (0–49), respectively. In all pts treated at RP2D in TRIDENT-1 (n = 426), dizziness (62%; grade ≥3, 3%) was the most common treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 51% of pts (29% treatment-related AEs). Treatment discontinuation rate due to TEAEs was 7% (3% due to treatment-related AEs). In TRIDENT-1, with 8.7 mo minimum follow-up, repotrectinib showed robust responses and durable clinical activity in both TKI-naïve and -pretreated pts with NTRK+ solid tumors, including NSCLC. Repotrectinib safety at RP2D was manageable, consistent with prior reports.Table: 1372PRepotrectinib in NTRK+ solid tumorsNTRK+ solid tumorsaTKI-naïve (n = 40)TKI-pretreated (n = 48)Efficacy, % (95% CI)cORRb58 (41–73)50 (35–65)12-mo DOR86 (71–100)39 (16–62)12-mo PFS56 (40–72)22 (8–36)NTRK+ solid tumors by prior TKIccORR,b % (95% CI)Prior larotrectinib (n = 23)—43 (23–66)Prior entrectinib (n = 24)—54 (33–74)NTRK+ solid tumors with solvent front mutations(n = 25)Efficacy, % (95% CI)cORRb—60 (39–79)12-mo DOR—33 (7–58)12-mo PFS—21 (4–39)aTumors included NSCLC (52% TKI-naïve; 29% TKI-pretreated), salivary gland cancer (8%; 17%), thyroid cancer (12%; 8%), soft tissue sarcoma (8%; 12%); others <10% each. bPer RECIST v1.1. cMay have received 1-2 prior TKI. Open table in a new tab

Patients with advanced NSCLC without EGFR-activating mutations (EGFRm) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO). HER3-DXd is an antibody drug conjugate consisting of a fully human anti-HER3 mAb attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Here we present updated results, previously presented at ASCO 2022, in patients without tumor EGFRm who progressed after PBC ± IO treatment.

Aberrations of the ALK oncogene drive tumor cell proliferation, survival, and metastasis in multiple adult and pediatric cancers. ALK gene fusions are detected in ~5% of advanced non-small cell lung cancers (NSCLC); among these patients, the incidence of central nervous system (CNS) metastases at diagnosis is ~40%. Although 5 tyrosine kinase inhibitors (TKIs) are approved by the FDA and EMA for ALK-positive NSCLC, therapeutic limitations remain, such as acquired resistance due to secondary and compound ALK mutations and/or neurologic adverse events attributed to off-target inhibition of TRK. NVL-655 is a novel, brain-penetrant ALK-selective TKI that exhibits preclinical activity against diverse ALK fusions and mutations, including G1202R and G1202R compound mutations, while sparing inhibition of TRK. The ALKOVE-1 study is evaluating the safety and preliminary activity of NVL-655 in patients with solid tumors harboring oncogenic ALK alterations, including those with acquired ALK resistance mutations and CNS metastases. ALKOVE-1 consists of a phase I dose escalation followed by a phase II expansion in cohorts defined by tumor type and prior therapies. Phase I includes adult patients with any solid tumor type harboring an oncogenic ALK gene fusion or activating mutation (by local testing), including ALK fusion-positive NSCLC after ≥ 1 prior 2nd or 3rd generation ALK TKI. Prior platinum-based chemotherapy and/or immunotherapy, CNS disease without progressive neurological symptoms or increasing corticosteroid doses, and evaluable but non-measurable disease are allowed. Patients will receive NVL-655 by daily oral administration. Primary phase I objectives are to determine the NVL-655 recommended phase II dose and, if applicable, maximum tolerated dose. Additional objectives include evaluation of safety/ tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-655. Longitudinal analysis of circulating tumor DNA will be performed, including ALK mutation profiling and other relevant biomarkers. The phase I portion of the study is ongoing. NCT05384626 (May 20, 2022). Nuvalent, Inc. Nuvalent. Inc.

Osimertinib (osi) is the current first-line therapy for patients (pts) with metastatic EGFR-mutant NSCLC. Combination of anti-VEGF with EGFR inhibitors has a potential to prolong progression-free survival (PFS).

9017 Background: Patients (pts) with advanced NSCLC without EGFR-activating mutations ( EGFRm) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously published efficacy and safety data from a study of HER3-DXd in EGFRm NSCLC after failure of EGFR tyrosine kinase inhibitor (TKI) therapy. Here we present results in pts without EGFRm who progressed after PBC ± IO treatment. Methods: This ongoing phase 1 dose expansion study included a cohort of pts with advanced NSCLC without EGFRm who received prior PBC ± IO (NCT03260491). Pts with stable brain metastases were eligible, as were pts with non- EGFR oncogenic alterations and prior targeted therapy. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS, and safety. Results: At the Mar 26, 2021, data cutoff, 47 pts had been treated with HER3-DXd 5.6 mg/kg IV every 3 wk; 17 pts had an identified driver genomic alteration (4 KRAS and 1 NRAS mutations, 4 EGFR Ex20ins, 3 ROS1 and 2 ALK fusions, and 3 other). Median age was 62 y (range, 29-79 y); 53% of pts were female; 17% had squamous NSCLC. Median follow-up was 9.5 mo (range, 3.7-19.1 mo). Median number of prior anticancer regimens in the advanced setting was 3 (range, 0-8). Median treatment duration on study was 4.1 mo (range, 0.7-13.6 mo); treatment was ongoing in 11 pts (23%) at data cutoff. Confirmed ORR by BICR was 28% (13/47 pts; 95% CI, 16%-43%; 13 PRs, 22 SD). Median DOR was 5.7 mo (95% CI, 3.7-10.7 mo) and median PFS was 5.4 mo (95% CI, 3.9-12.7 mo). Among pts with identified driver genomic alterations, 35% (6/17) had a confirmed response by BICR, including 3 of 5 pts with KRAS/NRAS mutations and 2 of 2 with ALK fusions. Among pts without identified driver genomic alterations, 23% (7/30) had a confirmed response by BICR. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (26%), thrombocytopenia (15%), and fatigue (15%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (9%; 0 grade ≥3). Four pts (9%) had TEAEs associated with treatment discontinuation. No drug-related deaths occurred. Conclusions: These data show promising clinical activity in pts with NSCLC without EGFRm, including pts with other identified driver genomic alterations. Updated results from this study will be presented. The overall safety profile was similar to that previously reported in pts with EGFRm NSCLC. A phase 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC is ongoing (NCT04619004). Clinical trial information: NCT03260491.

HER2 mutation is a newly established actionable target in non-small cell lung cancer (NSCLC) with trastuzumab-deruxtecan (T-DXd) as the only approved targeted therapy for patients as 2nd line therapy. There is still an unmet medical need for patients after platinum-based chemotherapy and T-DXd. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 mutations and is being studied in a multi-cohort, multicenter, Phase 2 study (ZENITH20). Here, we present the efficacy and safety results of poziotinib in NSCLC patients harboring HER2 exon 20 mutations who previously received at least two lines of systemic therapies, including a platinum-based regimen.

DESTINY-Lung01 (NCT03505710) showed encouraging and consistent antitumor activity for T-DXd in heavily pretreated patients with HER2-overexpressing (immunohistochemistry [IHC] 3+/2+) NSCLC. We investigated associations between baseline gene mutations using ctDNA and clinical outcomes in these patients (data cutoff, May 2021). Among 90 patients in the DESTINY-Lung01 HER2-overexpressing cohorts, 85 had baseline ctDNA samples analyzed at Guardant Health OMNI. Activating mutations in key oncogenes (EGFR, RAS, BRAF) and other genes of interest at baseline were assessed for their association with clinical efficacy (objective response rate [ORR] and progression-free survival [PFS]) with T-DXd treatment (cohort 1, 6.4 mg/kg [N = 49]; cohort 1a, 5.4 mg/kg [N = 41] every 3 weeks); analyses were not adjusted for baseline characteristics. The 85 evaluable patients had an ORR of 27.1% (95% CI, 18.0-37.8) and a median PFS (mPFS) of 5.9 months (95% CI, 4.5-7.4). Activating mutations were identified in EGFR (15 patients [17.6%]: 7 T790M, 7 L858R, 1 S768I, 4 E746_A750del, 2 G719A), KRAS (20 patients [23.5%]), NRAS (1 patient [1.2%]), and BRAF (1 patient [1.2%]). 13 of the 15 patients with EGFR-activating mutations had prior EGFR tyrosine kinase inhibitor treatment. No clear effects of EGFR- and RAS-activating mutations on ORR and mPFS were observed; however, mutations in STK11 and KEAP1 were associated with significantly shorter mPFS (Table). Baseline ctDNA analysis showed that the presence of activating mutations in EGFR, KRAS, or NRAS did not impact the clinical efficacy of T-DXd in patients with HER2-overexpressing NSCLC whereas mutations in STK11 and KEAP1 were associated with shorter mPFS. Updated results will be presented (data cutoff, December 2021).Table: 151PEfficacy according to mutation statusN = 85Mut nORR WT % (95% CI)ORR Mut % (95% CI)mPFS WT Months (95% CI)mPFS Mut Months (95% CI)Key oncogenesEGFR1527.1 (17.2-39.1)26.7 (7.8-55.1)6.7 (4.5-7.5)4.6 (1.3-NA)RASa2126.6 (16.3-39.1)28.6 (11.3-52.2)6.7 (4.2-7.5)4.6 (1.4-NA)Other selected genesbSTK111129.7 (19.7-41.5)9.1 (0.2-41.3)7.0 (5.4-8.3)1.2 (0.5-2.8)KEAP11129.7 (19.7-41.5)9.1 (0.2-41.3)6.7 (5.4-8.3)1.4 (0.6-2.4)ARID21129.7 (19.7-41.5)18.2 (2.3-51.8)6.7 (5.4-10.5)3.1 (1.2-6.7)LRP1B3226.4 (15.3-40.3)28.1 (13.7-46.7)7.2 (5.4-15.5)4.2 (1.5-6.7)Mut, mutant; WT, wild-type. aKRAS/NRAS. bTop 4 genes based on log rank test significance for PFS. Open table in a new tab