Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti–programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) ...investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation–positive advanced NSCLC and disease progression after EGFR-TKI therapy.
Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.
CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease–like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% grade ≥3 in 6% of patients) in the osimertinib arm and rash (67% grade ≥3 in 0 patients) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.
Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.
Background
This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M‐positive advanced ...non–small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum‐pemetrexed according to the plasma T790M status.
Methods
Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next‐generation sequencing (NGS; Guardant360, Guardant Health).
Results
With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M‐positive vs 39 mm for T790M‐negative; P < .0001) and the presence of extrathoracic disease (58% for M1b‐positive vs 39% for M0‐1a‐positive; P = .002). Progression‐free survival (PFS) was prolonged in randomized patients (tissue T790M‐positive) with a T790M‐negative cobas plasma result in comparison with those with a T790M‐positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum‐pemetrexed groups (median, 5.6 vs 4.2 months).
Conclusions
PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M‐positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
This exploratory analysis of the AURA3 study demonstrates that plasma‐based platforms (cobas EGFR Mutation Test v2, next‐generation sequencing, and droplet digital polymerase chain reaction) are suitable for epidermal growth factor receptor mutation detection in routine clinical practice. In patients with tissue T790M‐positive non–small cell lung cancer, the absence of detectable plasma T790M is associated with longer progression‐free survival, which may be attributed to a lower disease burden.
Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis ...evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).
Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation‐positive (EGFRm) non‐small cell lung cancer (NSCLC). Osimertinib is a third‐generation, ...irreversible, EGFR‐tyrosine kinase inhibitor that potently and selectively inhibits EGFR‐sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open‐label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN‐BM) assessed 11Cosimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90‐min 11Cosimertinib PET examinations were acquired together with metabolite‐corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast‐enhanced MRI was performed at screening and after 25–35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51–77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmaxbrain) 22 min (median, Tmaxbrain) after injection. Total volume of distribution (VT) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%–95% reduction in total BMs volume after 25–35 days of osimertinib 80 mg q.d. treatment. The 11Cosimertinib crossed the blood–brain and brain‐tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.
2520 Background: MCLA-145, a human common light chain bispecific antibody targeting CD137 and the PD-1/PD-L1 axis, is designed to enhance both antigen-mediated T cell activation via CD137 ...costimulation, and blockade of inhibitory PD-L1. Interim data from the ongoing phase 1 study (NCT03922204) are presented. Methods: Patients (pts) with PD-L1 ≥1% advanced/metastatic solid tumors received MCLA-145 IV as monotherapy Q2W/Q3W in 21/28-d cycles respectively, or in combination with pembrolizumab 200 mg Q3W in 21-d cycles. Pts enrolled in combination had cancers that either relapsed after PD-(L)1 therapies or were immunotherapy naïve. Primary objectives are safety, tolerability and dose-limiting toxicity (DLT) of MCLA-145 alone or combined with pembrolizumab, and determination of the recommended dose for expansion (RDE). Secondary endpoints include efficacy, pharmacokinetics, pharmacodynamics (PD) and immunogenicity. Results: As of a December 4, 2023 data cutoff, 72 pts with 26 cancer types were treated; 25% of pts had non-small cell lung cancer (NSCLC). 3 pts were continuing combination therapy. Monotherapy: 53 pts (median age 60 y, 49% male) were treated across 8 dose levels (47 pts 0.4-75 mg Q2W, 6 pts 40 mg Q3W). Median number of cycles was 2 (range 1-39). 6 pts had DLTs in the 25-75 mg dose range (febrile neutropenia 2 pts, hemolytic anemia, myositis, ALT/AST increase, neutrophil/platelet decrease 1 pt each). Most common adverse events (AEs; all grades/G3-4) were fatigue (51%/4%), decreased appetite (34%/2%), dyspnea (32%/0%), anemia (30%/9%), ALT/AST increase (25%/11%), and pyrexia (25%/0%). The incidence of any G3-4 AE was lower with 40 mg Q3W than across all Q2W dose levels (33% vs 66%). Combination: 19 pts (median age 61 y, 47% male) were treated with MCLA-145 10, 25 or 40 mg plus Q3W. Median number of cycles was 5 (range 1-16). No DLTs occurred. Most common AEs (all grades/G3-4) were fatigue (58%/11%), cough (42%/0%), constipation (32%/0%) and ALT/AST increase (21%/11%). The RDE was established at 40 mg Q3W for both monotherapy and combination. Preliminary antitumor activity was observed with monotherapy (52 evaluable pts): 5 partial responses (PRs) in glioblastoma (lasting >3 y), sarcoma, cervical, anal, and gastric cancer (treated for 2-11 mo); and combination (19 evaluable pts): 1 PR in Merkel cell carcinoma (treated 12+ mo), 1 complete response in PD-L1+ NSCLC (treated 6+ mo), both after prior immunotherapy. Disease control rate was 37% with monotherapy and 68% with combination. Exposure was dose-dependent with a terminal half-life of 69 h at 75 mg. Measure of peripheral blood Ki67+ CD8 T cells supports maximal PD activity at 40 mg. Conclusions: MCLA-145 given alone or in combination with pembrolizumab had a well-tolerated and manageable safety profile with encouraging clinical activity, including in pts who relapsed after PD-(L)1 therapies. Clinical trial information: NCT03922204 .
8583 Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. In particular, splice-site alterations ...resulting in the loss of transcription of exon 14 in the oncogenic driver c-MET ( METex14 skipping mutations) occur in ~3% of NSCLC and lead to oncogenic MET activation. MCLA-129 is a bispecific antibody that targets EGFR and c-MET with multiple mechanisms of action, including inhibition of EGFR and c-MET signaling, antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity. In the dose escalation part of a phase 1/2 trial (NCT04868877), the initial recommended phase 2 dose of MCLA-129 monotherapy was determined to be 1500 mg every 2 weeks (Q2W) with 28-day cycles. Significant tumor shrinkage was observed in one patient with METex14 NSCLC previously treated with multiple chemotherapy agents and the c-MET tyrosine kinase inhibitor (TKI) capmatinib. Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of the trial. Methods: Pts with advanced/metastatic METex14 NSCLC Pts received MCLA-129 1500 mg IV Q2W, until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. Primary endpoint: investigator-assessed ORR (RECIST v1.1), in pts with measurable disease, ≥2 MCLA-129 cycles, and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned. Results: As of December 1, 2023, 15 pts were dosed. The median age was 72 years (range 61-83), 40% were male, and 13%/87% of pts had ECOG performance status 0/1 respectively. The trial is ongoing; further analysis of safety and efficacy is planned with a later data cutoff date and will be presented at the meeting. Conclusions: MCLA-129 is being evaluated as monotherapy for the treatment of patients with locally advanced/metastatic c-MET exon 14 skipping NSCLC. Clinical trial information: NCT04868877 .
Osimertinib is a potent, third‐generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR‐TKI ...sensitizing and EGFR T790M resistance mutations. It is approved for first‐line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M‐positive advanced NSCLC whose disease has progressed on or after EGFR‐TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P‐glycoprotein substrate) following single‐ and multiple‐dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR‐TKI therapy. This open‐label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3‐ to 7‐day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56% (90% confidence interval CI, 35.4–78.6) and 76% (90%CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2–45.8) and 25% (90%CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P‐glycoprotein inhibitor.
Purpose
To determine the recommended dose and antitumor activity of single-agent elisidepsin as a 24-h intravenous (i.v.) infusion fortnightly biweekly, d1 and 15 every 4 weeks (q4wk); Arm A, ...dose-intensity strategy or as a 3-h i.v. infusion weekly (d1, 8, 15 and 22 q4wk; Arm B, dose-density strategy) in adult patients with unresectable, locally advanced or metastatic pretreated esophageal, gastroesophageal junction and gastric cancer.
Methods
Patients were randomized to one of two elisidepsin dosing schedules. Phase Ib starting doses were 8.0 mg flat dose (FD) in Arm A and 3.0 mg FD in Arm B. Phase II subsequently explored antitumor activity of both dosing schedules at the respective recommended doses.
Results
Forty-four patients received elisidepsin: 12 in stage Ib and 32 in stage II. The recommended doses were defined as 10 mg FD (Arm A) and 3.75 mg FD (Arm B). Both schedules were well tolerated. Most adverse events were mild or moderate, reversible and predictable with no meaningful differences between schedules. The pharmacokinetic profiles of both schedules were similar to those reported previously in patients with solid tumors treated with a comparable dose. An interim analysis found tumor control in one patient receiving elisidepsin fortnightly, and in none given elisidepsin weekly; patient accrual was therefore discontinued due to lack of efficacy.
Conclusions
Both schedules at the recommended doses presented an acceptable safety profile, but lack of response means that we do not recommend further evaluation of single-agent elisidepsin as chemotherapy for unresectable, locally advanced or metastatic gastroesophageal cancer.
PDF
