Search

This open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level enriched for EGFRmt could be overcome by emibetuzumab, an antibody against MET. Although some responses were seen, the trial did not meet its primary endpoint. Introduction: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. Patient and Methods: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (>= 10% of cells expressing MET at >= 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in >= 60% of cells >= 2+ (MET > 60%). Results: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET >= 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). Conclusion: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit. (C) 2022 Elsevier Inc. All rights reserved.

Background: More than 60% of under-served patients with lung cancer first present with advanced/metastatic disease. Randomized trials have shown that LDCT of chest reduces lung cancer mortality but under-served populations have been excluded from these studies because of financial, geographic, insurance and access problems. We have tested the first mobile LDCT units and demonstrated improved access. We report a shift to earlier stage at diagnosis and potential cures in a large under-served population that includes African American, Hispanic/LatinX and Native American subjects. Methods: We developed two coaches fitted with portable 32 slice low-dose CT scanners to screen uninsured and under-served heavy smokers for lung cancer in an IRB-approved program ("The Oncologist", 2019). All films were reviewed by a central panel (using LUNG RADS protocol). Medicare patients were excluded because their insurance covers LDCT lung screening (but it should be noted that the elderly population is at increased risk for lung cancer, leading to a negative case selection bias). Results: We initially screened 1200 uninsured/under-insured subjects, mean age 61 years (range 55-64), with average pack year history of 47.8 (range 30- >150); 61% male; 18% Black, 3% Hispanic/LatinX, 50% had intercurrent cardiovascular disease and COPD seen on LDCT. We have additionally screened 574 cases, including 51 Native Americans (in a structured assessment of one tribe). Of the Native Americans, 5 had LUNG RADS 3-4 (high risk) lesions, but no cancers have been identified to date. For the total series of 1774 subjects with age-related negative case selection bias, 42 lung cancers have been identified (2.4%), 26 of which were treated with curative intent (62%) via surgery, radiation, or chemo-radiation. Only one patient of 18 treated with curative intent in the first series of 30 lung cancers has relapsed to date (median follow up 3 years, with 5 without evidence of disease beyond 3.5 years). These data confirm a shift to detection of early-stage lung cancer in this large under-served population, with an apparent potential for cure. Conclusion: Mobile LDCT yields a higher screening rate for under-served patients than prior hallmark trials, with a consequent shift to early-stage detection of lung cancer, with sustained treatment-induced complete remissions beyond 4 years. This approach could be applied to improve national lung cancer survival in the under-served. Citation Format: Derek Raghavan, Darcy Doege, Mellisa Wheeler, Kia Dungan, John Doty III, Glenn Hickman, Kathryn Mileham, Daniel Carrizosa. Screening under-served populations by mobile low dose computerized tomography (LDCT) scans results in stage shift with potential cures: Time for a change in health policy? [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR006.

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Background: The anti-TIGIT antibody vibo in combination with pembro was well tolerated across all doses in the dose-escalation phase of the ongoing phase 1 study in pts with advanced solid tumors (NCT02964013); promising antitumor activity of vibo + pembro was observed in anti-PD-1/PD-L1-naive NSCLC. We present initial results of the dose-expansion phase in pts with advanced cervical cancer naive to PD-1/PD-L1 inhibitors. Methods: Pts with histologically confirmed, locally advanced, or metastatic cervical cancer who failed prior standard-of-care chemotherapy or who experienced early progression on definitive chemoradiation and were naive to PD-1/PD-L1 inhibitors were randomly assigned 1:1 to receive 1 of 2 doses of vibo (200 or 700 mg) + pembro (200 mg) Q3W for ≤35 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Primary end points were safety and tolerability. Secondary and exploratory end points included ORR, DOR, and PFS by investigator review per RECIST v1.1. Results: Median age of the 80 pts with cervical cancer was 49 y; 58% had an ECOG PS of 1; 53% received ≥2 prior lines of therapy; and 61% had PD-L1-positive tumors. 41 pts received vibo 200 mg, and 39 received vibo 700 mg. Median follow-up was 12 mo (range, 5-26). Treatment-related AEs (TRAEs) occurred in 27 pts in each treatment group (66%, vibo 200 mg; 69%, vibo 700 mg). The most frequent TRAEs (≥15%) were rash (22%), increased lipase (17%), and pruritus (17%) with vibo 200 mg + pembro and pruritus (28%), pyrexia (21%), rash (15%), and fatigue (15%) with vibo 700 mg + pembro. Grade 3 or 4 TRAEs occurred in 29% (vibo 200 mg + pembro) and 18% (vibo 700 mg + pembro). No deaths due to TRAEs were reported. Efficacy is reported in the Table. Conclusions: Vibo + pembro was safe in pts with advanced cervical cancer. Antitumor activity was comparable between the 2 doses of vibo studied and responses were observed irrespective of PD-L1 status. Based on these data, the RP2D for vibo remains 200 mg Q3W. Efficacy By Treatment Group By PD-L1 Statusa Vibo 200 mg + Pembro n = 41 Vibo 700 mg + Pembro n = 39 PD-L1-positive n = 49 PD-L1-negative n = 21 Confirmed ORR, % (95% CI) 15 (6-29) 23 (11-39) 20 (10-34) 14 (3-36) CR, n (%) 2 (5) 5 (13) 6 (12) 1 (5) PR, n (%) 4 (10) 4 (10) 4 (8) 2 (10) SD, n (%) 12 (29) 7 (18) 14 (29) 3 (14) PD, n (%) 18 (44) 19 (49) 20 (41) 12 (57) Median DOR, months (range)b Not reached (10 to 31+) Not reached (4+ to 35+) Not reached (4+ to 35+) Not reached (21 to 27+) Median PFS, months (95% CI) 2 (2-4) 2 (2-4) 4 (2-4) 2 (1-4) CR, complete response; DOR, duration of response; PD, progressive disease; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. aPD-L1 status was unknown in 10 patients; data were pooled across treatment groups. PD-L1 positivity was defined as combined positive score (CPS) ≥1 or when CPS was missing, as tumor proportion score ≥1% or mononuclear immune cell density score ≥2. b“+” indicates no PD present at the time of the last disease assessment. Citation Format: Ronnie Shapira-Frommer, Ruth Perets, Mark Voskoboynik, Kathryn Mileham, Adnan Nagrial, Brian Stein, Vincent Chung, Martin Gutierrez, Diana Chen, Tanya Keenan, Mohini Rajasagi, Jane Healy, Sun Young Rha. Safety and efficacy of vibostolimab (vibo) plus pembrolizumab (pembro) in patients (pts) with cervical cancer naive to PD-1/PD-L1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT508.