Advanced EGFRm Research Articles

Real-world outcomes among patients with advanced EGFRm NSCLC previously treated with osimertinib and platinum-based chemotherapy.

396 Background: For patients with advanced EGFR-mutant non-small cell lung cancer (EGFRm aNSCLC) progressing after osimertinib (OSI) and platinum-based chemotherapy (PBC) no uniformly accepted standard of care exists. The study was to provide updated results with a refreshed dataset for a previous study describing clinical outcomes of treatment regimens initiated after OSI and PBC in real-world patients with similar baseline characteristics to those in HERTHENA-Lung01 (HL-01), a multinational single-arm phase II trial evaluating the safety and efficacy of patritumab deruxtecan [1] . Methods: This study analyzed data from the US nationwide Flatiron Health electronic health record–derived aNSCLC de-identified database from approximately 280 US cancer clinics (~800 sites of care). Adult patients with an aNSCLC diagnosis (after 01 January 2011) and prior treatment with OSI and PBC, who initiated a subsequent line of therapy (index LOT) before 01 August 2022 were included in the study. Patients were chosen to closely match the HL-01 eligibility criteria (documented exon 19 deletion or L858R mutation; Eastern Cooperative Oncology Group Performance Status of 0 or 1; and absence of relevant comorbidities at index date). To further balance patient characteristics, the sample was propensity-score (PS) weighted based on nine covariates. Real-world overall survival (rwOS), progression-free survival (rwPFS) and overall response (rwORR, defined as partial or complete response with ≥2 assessments ≥28 days apart) were assessed from the start of the index LOT with corresponding 95% confidence intervals (CI). Results: 179 patients in the database fulfilled the eligibility criteria, increasing the sample size by 42% compared to the previous study 1 . Median age of the unweighted sample at index was 68 years, 65.9% of patients were female, 40.2% had a history of smoking and 26.3% received more than 3 LOTs prior to the index LOT. In the PS-weighted cohort (standard mean difference of all covariates was ≤0.127) the median rwOS was 9.1 months (95% CI: 7.3 – 11.3) and median rwPFS was 3.5 months (95% CI: 2.7 – 4.6). For a subsample of 75 patients with qualifying response assessments, rwORR was 12.7% (95% CI: 4.8 – 25.7). Conclusions: These observations in patients with EGFRm NSCLC after OSI and PBC demonstrate a limited clinical benefit with currently available therapies. The results are consistent with the previously published study and increase precision of the outcome estimates 1 . They highlight the high unmet need and provide further context on clinical outcomes of HL-01 trial results. [1] Patel et al. Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy. 2023 Sep 9-12 Singapore. P2.31.

Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC

IntroductionBrain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression. MethodsA prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group. ResultsA total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6–49.0), 31% (95% CI:10.6–53.9), and 31% (95% CI:10.8–54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6–49.0), 52% (95% CI:23.8–74.2), and 57% (95% CI:24.9–79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. ConclusionsNo relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.

Mutational Prognosis of Survival by Liquid Biopsy in Advanced EGFRm NSCLC

Mutational Prognosis of Survival by Liquid Biopsy in Advanced EGFRm NSCLC

Tepotinib + osimertinib for EGFR mutant (EGFRm) NSCLC with MET amplification (METamp) after first-line (1L) osimertinib.

9021 Background: METamp is a common resistance mechanism developed in patients (pts) with EGFRm NSCLC treated with osimertinib. MET tyrosine kinase inhibitors (TKIs) such as tepotinib may be effective in treating these pts after osimertinib. Here we report interim data from the INSIGHT 2 study evaluating tepotinib + osimertinib in EGFRm NSCLC with METamp previously treated with osimertinib. Methods: In this open-label Phase II study (INSIGHT 2, NCT03940703), pts with advanced EGFRm NSCLC with METamp after progression on 1L osimertinib received tepotinib 500 mg (450 mg active moiety) + osimertinib 80 mg once daily. METamp was centrally detected in tissue biopsy (TBx) by FISH ( MET gene copy number [GCN] ≥5 and/or MET/ CEP7 ≥2) and/or in liquid biopsy (LBx) by NGS ( MET plasma GCN ≥2.3; Archer). The primary endpoint was objective response by Independent Review Committee in tepotinib + osimertinib treated pts with centrally detected METamp by FISH (FISH+). Efficacy data are reported for pts with ≥3 months’ follow-up, and safety for all pts who received one dose of tepotinib + osimertinib by Sep 26, 2022 (data cut-off). Results: Among 472 pts prescreened, 451 pts had METamp results by either TBx FISH and/or LBx NGS, of which 175 (38.8%) were positive for METamp. 122 pts received tepotinib + osimertinib (median age 61 years [range 20–84], 59.8% female, 59.8% Asian, 68.0% never smoker, 72.1% ECOG PS 1). In 98 pts with FISH METamp (29.6% had &lt; 12 months on 1L osimertinib; median GCN 11 [range 5.0–50.6]; mean ± SD sum of target lesion diameters [SOLD] 73.2 ± 47.1 mm), objective response rate (ORR) was 43.9% (95% CI 33.9, 54.3), median (m) DOR was 9.7 months (95% CI 5.6, ne), mPFS was 5.4 months (95% CI 4.2, 7.1), and mOS was not reached (95% CI 11.1, ne). Of the 98 pts, treatment is ongoing in 42 pts. In 31 pts with METamp detected by LBx NGS, of which 24 were also FISH+ (mean ± SD SOLD 93.9 ± 51.4 mm), ORR was 51.6% (95% CI 33.1, 69.8), mDOR was 5.6 months (95% CI 2.9, ne), mPFS was 4.6 months (95% CI 2.7, 6.9), and mOS was not reached (95% CI 6.8, ne). Of 122 pts treated with tepotinib + osimertinib, any grade treatment-related AEs were reported by 99 (81.1%) pts including 34 (27.9%) Grade ≥3. Most common ( &gt; 15% pts) treatment-related AEs included diarrhea 46.7% (0% Grade ≥3), peripheral edema 34.4% (4.1% Grade ≥3), paronychia 20.5% (0.8% Grade ≥3), decreased appetite 18.0% (3.3% Grade ≥3), and nausea 16.4% (1.6% Grade ≥3). Treatment-related AEs led to a dose reduction in 21 (17.2%) pts, following either or both treatments and led to treatment discontinuation in 7 pts (5.7%). Conclusions: In this interim analysis of INSIGHT 2, tepotinib + osimertinib was highly active with durable responses, and was well tolerated in pts with EGFRm NSCLC with METamp after progression on 1L osimertinib. Tepotinib + osimertinib provides a potential chemotherapy-sparing oral targeted therapy option in this population with a high unmet need. Clinical trial information: NCT03940703 .

BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study.

9011 Background: Despite improved frontline OSI treatment outcomes, patients (pts) with advanced EGFRm NSCLC inevitably progress, with worse outcomes in the EGFR L858R subgroup (median PFS of 14.4 vs 21.4 mo in pts with exon 19 deletions). BLU-945 is an investigational, next-generation, oral tyrosine kinase inhibitor (TKI) that targets common EGFR-activating and T790M and C797X resistance mutations, while being selective against EGFR wild type (WT). Preclinically, BLU-945 in combination (combo) with OSI had enhanced potency on L858R and extended antitumor response durability versus OSI alone. SYMPHONY (NCT04862780) is an ongoing first-in-human phase 1/2 study of BLU-945 monotherapy (mono) or combo with OSI. Methods: In the phase 1 dose escalation, pts (aged ≥18 y; metastatic EGFRm NSCLC; ECOG PS 0–1; treated with ≥1 EGFR TKI) received BLU-945 mono starting at 25 mg QD. Pts progressing on OSI could receive BLU-945 with 80 mg OSI starting at 50% of the highest safe BLU-945 mono dose. Each dose escalation followed a Bayesian Optimal Interval design. Safety, including dose-limiting toxicities (DLT), PK, and circulating tumor DNA (ctDNA) mutational status were assessed. Results: As of Jan 6, 2023, 108 pts received BLU-945 mono (25–600 mg QD; 100–300 mg BID). Pts had a median of 3 lines of prior therapy and were genomically complex with ctDNA detectable EGFR on-target and/or off-target resistance alterations (46%) at baseline. DLTs included alanine transaminase (ALT) and aspartate transaminase (AST) elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, occurring at doses of ≥400 mg/d. The maximum tolerated dose was 500 mg/d. The most common AEs were nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%). Robust on-target EGFR activity was observed with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles at ≥400 mg/d doses, respectively. At ≥400 mg/d, 48% had tumor shrinkage, including partial responses (PRs). Twenty-five pts received BLU-945 (200–400 mg QD; 100–200 mg BID) combo with OSI. Pts had a median of 2 lines of prior therapy. The most common combo AEs were fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). Other EGFR WT AEs were dry skin (20%) and rash (8%). One DLT (Grade 4 pneumonitis) was reported in the BLU-945 300 mg QD with OSI group. Tumor reductions, including PRs in 2 pts progressing on OSI, were observed at ≥300 mg/d. Dose escalation is ongoing. Conclusions: BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line. Clinical trial information: NCT04862780 .

Abstract 1052: Background variability in plasma ctDNA levels in patients with advanced lung cancer in the absence of treatment

Abstract Introduction: Molecular response (MR) is defined as a reduction in circulating tumor DNA (ctDNA) levels between baseline and early on-treatment timepoint(s). MR is predictive of long-term outcomes in several advanced cancers treated with different therapeutic modalities. Common MR thresholds include reductions in ≥50%, or 100% (clearance) in ctDNA levels. A better understanding of the background variability in measured plasma ctDNA levels in the absence of therapy is required to enable improved interpretation of MR, especially as its use increases in drug development and clinical management. Methods: In the largest study of double baseline pre-treatment ctDNA samples reported to date, paired screening and pre-treatment cycle 1 day 1 (C1D1) samples (IQR: 8-24, median 17 days apart) from 360 patients with advanced EGFRm non-small cell lung cancer (NSCLC) from the FLAURA (1L, N=132) and AURA3 (2L, N=228) trials were compared to characterize background variability in ctDNA. ctDNA was quantified using NGS (Guardant Health G360 and OMNI) and ddPCR (Biodesix) assays. Various potential drivers of background variability, such as ctDNA quantification platforms, coverage, and number of variants at baseline were evaluated to better understand any underlying confounding effects. Results: Pre-treatment background variability was consistently observed in both AURA3 and FLAURA cohorts. Most of the variability reflected any increase in pre-treatment ctDNA in 28% (64/228) of cases in AURA3, and 13% (17/132) of cases in FLAURA. Variability reflecting a ≥50% decrease in pre-treatment ctDNA was observed in 8% (18/228) of cases in AURA3 and 9% (12/132) of cases in FLAURA, with only 2% of cases showing ctDNA clearance in AURA3 and 0% in FLAURA. Testing technical replicates sequenced a year apart and comparing ctDNA levels quantified with NGS v. ddPCR for potential sources of technical variability did not show large variability. Moreover, sources like cell-free DNA input, allele frequency levels, and days in between screening and C1D1 were tested but could not fully account for the variability observed. Conclusion: Although pre-treatment increases in ctDNA levels were expected in patients with advanced cancer, background variability also included reductions in ctDNA that may be confounded as MR. Understanding the impact of factors on the transient nature of ctDNA is key, but as momentum mounts to use ctDNA as a biomarker of therapeutic response, it is crucial to test and account for background variability rates to improve MR interpretability. Additional work is warranted to elucidate the background variability rate in other cancer types and settings. Citation Format: Diana M. Vega, Aleksandra Markovets, Christopher Abbosh, Katie Quinn, Kyle Chang, Sara Wienke, Ryan Hartmaier, Matthew Hellmann, J Carl Barrett, Darren Hodgson. Background variability in plasma ctDNA levels in patients with advanced lung cancer in the absence of treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1052.

Intermittent EGFR-TKI Therapy is Associated with Durable Response in Advanced EGFR-Mutant NSCLC: A Case Report

Madam S, who diagnosed to have stage IV lung adenocarcinoma with exon 21 L858R point mutation (T3N2M1a) was admitted for massive pericardial effusion in April 2016. She was ECOG 4 on admission. Her ECOG improved to 1 after pericardial tapping and initiation of free sample erlotinib 100 mg daily. Repeated CT thorax post treatment showed the disease was partial responded. Due to financial constraints, she had never bought any EGFR-TKI. She was given a free sample of erlotinib intermittently for total of 12 months followed by intermittent afatinib supply for 2 years. Due to this limited supply, she took half doses of afatinib by cutting a 40 mg tablet once every few days to sustain the continuation of cancer treatment. No major side effects were observed and she remained ECOG 0 with good weight gain. Up to her last clinic visit in September 2021, her PFS was more than 5 years. Intermittent doses of EGFR-TKI may prolong PFS in patients with advanced EGFRm+ NSCLC who has limited treatment options.

LBA58 Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: Second interim analysis of phase III ORIENT-31 study

The randomized, double-blind, phase 3 ORIENT-31 study was to evaluate sintilimab (sin, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo), vs chemo, in patients (pts) with EGFRm nsqNSCLC who progressed on EGFR TKIs therapy. The first interim analysis (IA) showed sin + IBI305 + chemo significantly improved progression-free survival (PFS) vs chemo alone (Lu, et al. Lancet Oncol 2022). Eligible pts were randomized (1:1:1 at the first stage and 2:2:1 at the second stage) into Arm A (sin + IBI305 + chemo), Arm B (sin + placebo [pb] 2 + chemo) and Arm C (pb1 + pb2 + chemo). Sin/pb1 (200 mg), IBI305/pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sin/pb1, IBI305/pb2 and pemetrexed. The primary endpoint was PFS assessed by IRRC per RECIST v1.1. Per prespecified statistical analysis plan, the second IA (reported here) aimed to evaluate the PFS between Arm B and Arm C, and the superiority conclusion of Arm A over Arm C has been achieved at the first IA. By data cutoff (Mar 31, 2022), 476 pts were randomized (Arm A/B/C: 158/158/160). Median age was 57.0 years. 37.0% pts had brain metastasis. Previously, 63.0% pts received 1st or 2nd generation (G) TKI with T790M-, 26.3% pts received 1st or 2nd and then 3rd G TKI with T790M+, and 10.5% pts received first-line 3rd G TKI. With a median follow-up of 13.1 months, median PFS (95% CI) by IRRC was 7.2 months (6.6, 9.3) in Arm A, 5.5 months (4.5, 6.1) in Arm B, and 4.3 months (4.1, 5.3) in Arm C. PFS was significantly improved in Arm B vs Arm C (HR 0.723, 95% CI: 0.552, 0.948; P=0.0181). Confirmed ORR by IRRC was 48.1%, 34.8% and 29.4% in Arm A, B and C respectively; DCR was 86.1%, 81.6% vs 75.6%; median DOR was 8.5 months, 7.4 months vs 5.7 months. Grade ≥3 treatment-emergent adverse events occurred in 59.5%, 46.2%, and 56.9% pts respectively. Sin combined with or without IBI305 and chemo significantly improved PFS in pts with advanced EGFRm nsqNSCLC who progressed on EGFR-TKI therapy, vs chemo alone.

EP08.02-138 SAFFRON: Ph3 Savolitinib + Osimertinib vs Chemotherapy in EGFRm NSCLC with MET Overexpression/Amplification Post-Osimertinib

Osimertinib is a potent, third-generation, irreversible, oral EGFR-TKI which has demonstrated efficacy in NSCLC and related central nervous system metastases. Osimertinib is the preferred first-line treatment in advanced EGFRm NSCLC; however, patients may develop resistance to osimertinib. MET overexpression and/or amplification is the most common acquired resistance mechanism to osimertinib. However, there is no approved targeted therapy for these patients; platinum-based chemotherapy remains the standard of care but has limited efficacy.

Effect of Gefitinib Combined with Chemotherapy in Patients with Advanced NSCLC: A Retrospective Cohort Study.

BackgroundThere are currently no methods for the treatment of reversible drug-resistant EGFR-TKI lung cancer in the clinical setting, and thus, the patients finally return to the currently used drugs. This study aimed to compare the efficacy of chemotherapy alone and gefitinib combined with chemotherapy in the treatment of non-small cell lung cancer (NSCLC) patients in advanced stage with the mutation of epidermal growth factor receptor (EGFR).MethodsA retrospective analysis was carried out on 120 patients with advanced EGFRm+ NSCLC who were divided into the control group (CG, received chemotherapy alone) or the observation group (OG, received chemotherapy and gefitinib) according to the treatment methods.ResultsComparison of the objective response rates (ORRs) showed no statistical significant difference between OG (36.92%) and CG (29.09%, P > 0.05), whereas in OG, disease control rate (DCR) was significantly increased in comparison with CG (P < 0.05). The medians of progression-free survival (PFS) and overall survival (OS) in OG were 8.0 months and 24.0 months, respectively, which were longer than 5.0 months and 18.0 months in CG (P = 0.031). The univariate analysis revealed that clinical stage of tumor (HR = 1.590, 95% CI: 1.097–2.343) was the prognostic factor for advanced lung cancer. Multi-factor Cox regression analysis revealed that clinical analysis was an independent prognostic factor (HR = 1.701, 95% CI: 1.099–2.632).ConclusionIn PFS patients, the OS rate was significantly improved, which was worth for clinical use.

Study of patient characteristics, treatment patterns, EGFR testing patterns and outcomes in real-world patients with EGFRm+ non-small cell lung cancer

Objective This retrospective, observational study examined patient characteristics, treatment patterns, testing patterns, and outcomes of US patients receiving first-/second- or third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods This study used an electronic health record-derived de-identified database. Eligible patients had advanced EGFRm+ non-small cell lung cancer. Descriptive statistics were used to describe demographic, clinical, and treatment characteristics. Logistic regression models were used to identify patient characteristics that were associated with the use of osimertinib vs. a first-/second-generation EGFR TKI. Kaplan–Meier methods were used for survival analysis. Results Of the 782 patients who received first-line (1L) therapy with first-/second-generation EGFR TKIs in cohort A, erlotinib was the most common (58%), and osimertinib was the most widely prescribed second-line (2L) therapy (52%). Of the patients who received 1L therapy with osimertinib, a greater range of treatments were prescribed in 2L. A third of patients treated with first-/second-generation EGFR TKIs underwent EGFR testing near the end of 1L, and 44% of these patients had T790M positive disease. The median time on targeted therapy (TTT) of the cohort was 11.1 months (95% confidence interval [CI] 9.7, 12.3), and the median overall survival from the start of 1L therapy was 23.5 months (95% CI 20.7, 24.8). Conclusions The majority of patients treated with first-/second-generation EGFR TKIs went on to receive osimertinib in the 2L setting, but overall, only a third of patients had received molecular testing at progression. Improved testing frequency is vital to inform treatment decisions.

P51.05 Sequential Afatinib and Osimertinib in Patients With Advanced EGFRm+ NSCLC and Acquired T790M: The Real-World UpSwinG study

The ErbB family blockers, afatinib and dacomitinib, and the third-generation EGFR TKI, osimertinib, confer significant clinical benefit versus first-generation EGFR TKIs (erlotinib and gefitinib) in patients with EGFR mutation-positive (EGFRm+) NSCLC. However, no prospective data exist directly comparing afatinib, dacomitinib and osimertinib. In terms of overall survival (OS), outcomes are highly dependent on the availability and implementation of subsequent therapy following acquired resistance to first-line therapy.

1238P AUTOMAN: A phase Ib/IIa study of osimertinib combined with anlotinib in EGFRm, treatment-naive advanced NSCLC patients

Osimertinib has been demonstrated superior PFS and OS compared to 1st-generation EGFR-TKIs. There is little information on efficacy and safety of combined therapy with Anlotinib which is an oral multiple-target TKI (inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret) in advanced EGFRm NSCLC patients.

Abstract CT163: CD73 inhibitor oleclumab plus osimertinib for advanced EGFRm NSCLC: First report of a Phase 1b/2 study

Abstract Background: Patients (pts) with EGFRm T790M-negative NSCLC with progressive disease (PD) on an EGFR TKI have limited therapy options. CD73 may promote immune evasion and is overexpressed in EGFRm NSCLC, suggesting the potential for combining CD73 blockers with EGFR TKIs. Oleclumab (MEDI9447) disrupts immune evasion by binding to CD73. This phase 1b/2, multicenter, dose escalation/expansion study (NCT03381274) evaluates the safety and efficacy of oleclumab plus osimertinib (osi) in locally advanced/metastatic EGFRm NSCLC. Methods: Pts had histologically or cytologically confirmed T790M-negative EGFRm NSCLC by local testing, a TKI-sensitive EGFR mutation (exon 19 del, L858R), ECOG PS 0-1, PD on a 1st or 2nd generation TKI, and no prior osi. Oleclumab 1500 mg (DL1) or 3000 mg (recommended Phase 2 dose, RP2D) IV Q2W + osi 80 mg PO QD were given until PD or intolerable AEs. Primary endpoints included AEs, SAEs and ORR by RECIST v1.1. DLTs were predefined and reviewed by a dose-escalation committee. Secondary endpoints included duration of response, disease control rate, PFS and OS. Results: As of November 9, 2020, 5 pts received DL1 and 21 pts received RP2D. Minimum follow-up was 44 wks. For the 5 pts receiving DL1, safety profile and response rate were generally similar to RP2D and no DLTs occurred. All of the 21 pts receiving RP2D had ≥1 treatment-emergent AE (TEAE), 38.1% had Grade 3/4 TEAEs and 23.8% had SAEs. Treatment-related AEs (TRAEs) occurred in 81.0% (19.0% Grade 3/4); none were SAEs or deaths. The most common TRAEs were rash (33.3%), stomatitis (28.6%), diarrhea (23.8%) and paronychia (23.8%). At data cutoff, 38.1% remained on treatment; 47.6% discontinued due to PD, with death, pt decision and AE (pneumonitis) as other causes. Response and survival for pts receiving RP2D are shown in Table 1. Conclusions: Oleclumab + osi was well tolerated at RP2D. Compared to T790M-negative EGFRm NSCLC pts in a prior study of osi monotherapy, ORR was similar (21% vs 19%) but mPFS was longer (2.8 vs 11.0 mos). Table 1.Disease response and survivalOutcomeN=21Best overall response, n (%)CR0PR4 (19.0)SD13 (61.9)PD3 (14.3)Not evaluable1 (4.8)ORR, n (%)4 (19)Median duration of response, months (range)Not assessable (9.2-11.1)Disease control rate, n (%)17 (81.0)Median PFS (95% CI), months11 (3.7-not evaluable)6-month PFS rate (95% CI), %63.5 (38.3, 80.7)9-month PFS rate (95% CI), %52.9 (29.0, 72.1)Median OS (95% CI), monthsNot reached (11.7-not evaluable)6-month OS rate (95% CI), %100 (100, 100)9-month OS rate (95%CI), %90.0 (65.6, 97.4) Citation Format: Dong-Wan Kim, Sang-We Kim, D. Ross Camidge, Naiyer A. Rizvi, Kristen A. Marrone, Xiuning Le, Collin Blakely, Keunchil Park, Gee-Chen Chang, Sandip Pravin Patel, Zachary A. Cooper, Rakesh Kumar, Ramin Samadani, Rebecca McCombs, Michael Pluta, Kevin Yufeng Wu, Suresh Ramalingam. CD73 inhibitor oleclumab plus osimertinib for advanced EGFRm NSCLC: First report of a Phase 1b/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT163.

Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).

9007 Background: Patients (pts) with advanced EGFRm NSCLC have limited treatment options after failure of EGFR TKI and platinum-based chemotherapy (PBC). 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 presented efficacy/safety data (median follow-up, 5.4 mo) from an ongoing study of HER3-DXd in EGFRm NSCLC after failure of EGFR TKI therapy. We now present extended follow-up of pts receiving the recommended dose for expansion (5.6 mg/kg IV Q3W). Methods: This Ph 1 dose-escalation/expansion study included pts with locally advanced or metastatic EGFRm NSCLC with prior EGFR TKI therapy (NCT03260491). Pts with stable brain metastases (BM) were allowed. 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 data cutoff (Sept 24, 2020), 57 pts were treated with HER3-DXd 5.6 mg/kg IV Q3W; median follow-up, 10.2 mo (range, 5.2-19.9 mo). Median number of prior anticancer regimens was 4 (range, 1-10). 100% had prior EGFR TKI (86% prior osimertinib [OSI]) and 91% had prior PBC. 47% had a history of BM. Median treatment duration was 5.5 mo (range, 0.7-18.6 mo); treatment was ongoing in 18 pts (32%). Confirmed ORR by BICR was 39% (22/57; 95% CI, 26.0%-52.4%; 1 CR, 21 PR, 19 SD) with 14/22 responses occurring within 3 mo of starting HER3-DXd. DCR was 72% (95% CI, 58.5%-83.0%). Median DOR was 6.9 mo (95% CI, 3.1 mo-NE), and median PFS was 8.2 mo (95% CI, 4.4-8.3 mo). Antitumor activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 ( EGFR C797S, MET or HER2 amp, and BRAF fusion). Among pts with prior PBC, ORR was 37% (19/52; 95% CI, 23.6%-51.0%); in pts with prior OSI and PBC, ORR was 39% (17/44; 95% CI, 24.4%-54.5%). Among 43 pts evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by IHC was 180 (range, 2-280). Median H-score (range; N) was 195 (92-268; 15) in pts with CR/PR, 180 (4-280; 15) with SD, 126.5 (2-251; 6) with PD, and 180 (36-180; 7) in pts unevaluable for best overall response. The most common grade ≥3 adverse events (AEs) were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (7%; 1 grade ≥3 [2%]; no grade 5). 6/57 pts (11%) had AEs associated with treatment discontinuation (none were due to thrombocytopenia). Conclusions: HER3-DXd 5.6 mg/kg IV Q3W demonstrated antitumor activity across various EGFR TKI resistance mechanisms in heavily pretreated metastatic/locally advanced EGFRm NSCLC. The safety profile was consistent with previous reports. A Ph 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC has been initiated (NCT04619004). Clinical trial information: NCT03260491.

Ph I/II study of oral selective AXL inhibitor bemcentinib (BGB324) in combination with erlotinib in patients with advanced EGFRm NSCLC: End of trial update.

9110 Background: AXL, a receptor tyrosine kinase, is over-expressed in many cancers, and has been identified as a marker of poor prognosis in NSCLC. AXL overexpression is implicated in development of resistance to EGFR inhibitors including erlotinib (Erl) and osimertinib. AXL inhibition by bemcentinib (Bem), a first-in-class, oral, selective and potent AXL kinase inhibitor, abrogates resistance to EGFR inhibitors in vivo. Bem is currently under evaluation as a monotherapy and in combination with EGFRi, CPIs and chemotherapy across several PhII trials. Methods: Phase I of this study was designed to confirm safety/tolerability of Bem in NSCLC pts as monotherapy and in combination with Erl in pts previously progressing on Erl (arm A). In Phase II, pts who had progressed on an approved EGFRi (arm B) or who were responding/stable on Erl in the 1L setting (arm C) were treated with Bem 200mg and Erl 150mg od to evaluate the safety and activity of the combination, assessing reversal or prevention of resistance to EGFR inhibition in these 2 groups, respectively. Plasma protein biomarker levels were sequentially measured using the DiscoveryMap v3.3 panel (Myriad RBM). Results: As of 7 Oct 2020, all arms have completed recruitment. Median exposure to Bem was 63d (mean: 200d, range: 2d-1175d). Treatment was generally well-tolerated. Common TRAEs (&gt;20% pts) were diarrhea (70%; G3 20%), nausea (50%; G3 0%), QTc prolongation (35%; G3 3%), vomiting (35%; G3 0%), and fatigue (25%; G3 5%). 1 unrelated G4, 0 G5 reported. In the run-in arm (5 female, median age 61 yrs [57-76]), 2/8 pts achieved SD for ̃1 yr, including 19% tumor shrinkage in 1 pt. In arm A (5 female, median age 58 yrs [38-67]), 1/8 pts (68 F) achieved tumor shrinkage of 38%, with treatment duration of 2 yrs until progression. A further 5 pts reported SD. In arm B, 11 pts (7 female, median age 63 yrs [49-78]) had received a median of 1 (0 - 4) prior lines of chemotherapy and a median of 2 prior lines of EGFRi. One achieved a PR (51M) and one a SD (62F) on the combination (CBR of 18%); durations on treatment were 1 yr, and 6 mos, respectively. Neither had EGFR T790M. mPFS was 1.4 mos. In arm C, 13 pts (10 female, median age 66 yrs [32-80]) were enrolled. 11/13 pts were evaluable for efficacy. 1 PR (58M) was reported with 47% tumor shrinkage, duration of treatment was 315d. 9 other pts achieved SD (CBR of 91%), including 4 (3 F/1 M, age range 64-71yrs) who continued on trial for 772+ to 1008+ d. mPFS is currently 12.2 mos. Protein biomarkers predictive of pt benefit upon Bem treatment are being explored. Conclusions: Bem with Erl combination is feasible and tolerable in NSCLC pts, with benefit was seen in a subset of pts who either progressed on an EGFRi or were receiving Erl concurrently in remission in the first line. Further studies of Bem + EGFRi are warranted to explore the potential benefits of this combination. Clinical trial information: NCT02424617.

Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC).

9047 Background: Upregulation of CD73 in multiple cancers increases adenosine production, leading to local immunosuppression. Oleclumab, a human IgG1λ mAb, inhibits CD73 function and may increase antitumor immunity. Initial data from a Phase I, first-in-human, dose-escalation and expansion study showed that oleclumab ± durvalumab had manageable safety and encouraging clinical activity in pts with advanced CRC or PDAC. We report updated safety and activity in these cohorts and the first results in an expansion cohort of pts with advanced EGFRm NSCLC. Methods: Previously treated pts with histologically or cytologically confirmed microsatellite stable CRC, PDAC, or EGFRm NSCLC received oleclumab 5–40 mg/kg (escalation) and 40 mg/kg (expansion) IV Q2W, alone (escalation only) or with durvalumab 10 mg/kg IV Q2W. The primary objective was safety; secondary efficacy objectives included objective response (OR) per RECIST v1.1 and duration of response (DoR). Results: 66 pts were enrolled in the escalation phase (35 CRC, 31 PDAC) and 126 in the expansion phase (42 CRC, 42 PDAC, 42 EGFRm NSCLC). At data cutoff (DCO; June 9, 2020), the median number of oleclumab doses was 4 in pts on monotherapy (range 1–26) and 4 in pts on combination therapy across both phases (range 1–76). In the escalation phase, there were no DLTs in pts on monotherapy or combination therapy; treatment-related adverse events (TRAEs) occurred in 54.8% of pts on monotherapy (Grade 3–4 in 7.1%) and 54.2% of pts on combination therapy (Grade 3–4 in 20.8%); fatigue was the most common TRAE with both regimens. No TRAEs resulted in death. In previous interim analyses before this DCO, no ORs were reported in the escalation phase. In the expansion phase, 5 pts were treated for ≥12 mos; 6 pts were ongoing at DCO. TRAEs occurred in 54.0% (Grade 3–5 in 15.1%); the most common TRAEs were fatigue (15.1%), diarrhea (9.5%), and rash (7.1%). One pt had a TRAE resulting in death (systemic inflammatory response syndrome). ORs were seen in 1 CRC pt (DoR 35.9+ mos [+ = ongoing response]), 2 PDAC pts (DoR 22.1+ and 28.6+ mos), and 4 EGFRm NSCLC pts (DoR range 5.6 to 15.7+ mos, median not reached; only 1 of the 4 pts had ≥25% programmed cell death ligand-1 [PD-L1]+ tumor cells). Nine CRC pts, 8 PDAC pts, and 9 EGFRm NSCLC pts had SD. Of 6 pts with matched biopsies who received combination therapy, 5 had increases in CD8+ T cells, PD-L1, and granzyme B. Baseline tumor CD73 expression and association with clinical response will be presented. Conclusions: Oleclumab ± durvalumab had a tolerable safety profile and combination therapy showed promising antitumor activity in EGFRm NSCLC. ORs and SD were durable, even in tumor types that are generally immunotherapy-resistant. Clinical trial information: NCT02503774.

P76.46 First-Line Osimertinib in Asian Patients with Advanced EGFR-Mutant Lung Cancer

Osimertinib is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). We describe the clinicopathological characteristics and clinical outcomes of advanced EGFRm+ NSCLC patients treated with first-line osimertinib.

A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer

BackgroundEGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFRm NSCLC was evaluated.MethodsThis Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.ResultsFrom dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0).ConclusionsDurvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFRm NSCLC.