Virtual Library
Start Your Search
Helena Yu
Author of
-
+
FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
FP14.03 - Osimertinib + Savolitinib in pts with EGFRm MET-Amplified/Overexpressed NSCLC: Phase Ib TATTON Parts B and D Final Analysis (ID 3312)
00:00 - 00:00 | Author(s): Helena Yu
- Abstract
- Presentation
Introduction
Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-TKI, that potently and selectively inhibits T790M and EGFR mutations (EGFRm), may overcome MET-based resistance to EGFR-TKIs in NSCLC. We present the final data from two TATTON expansion cohorts (TATTON Parts B and D); data cutoff 4 March 2020.
Methods
Adult patients with locally advanced/metastatic, MET-amplified/overexpressed, EGFRm NSCLC, and disease progression on a prior EGFR-TKI. Most patients had retrospective, central confirmation of MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥50% of tumour cells). In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, patients ≤55 kg received savolitinib 300 mg. In Part D, patients who had received no prior third-generation EGFR-TKI and were T790M-negative, received osimertinib plus savolitinib 300 mg. The primary endpoint was safety/tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and pharmacokinetics.
Results
In Parts B and D, 138 and 42 patients respectively, received treatment. Grade ≥3 adverse events (AEs) were reported in 62% and 50% of patients, in Parts B and D respectively; serious AEs were reported in 49% and 38% of patients, respectively. AEs led to discontinuation of savolitinib in 49 (36%) and 15 (36%) patients, and osimertinib in 24 (17%) and 8 (19%) patients, for Parts B and D, respectively. In Part B, seven patients died due to AEs; two cases were possibly treatment-related. In Part D, two patients died due to AEs; neither was considered treatment-related. PFS and ORR results are included in the Table. Pharmacokinetics of savolitinib and osimertinib were consistent with other patient populations in TATTON and previous studies.
Conclusion
Osimertinib plus savolitinib was generally well tolerated and the safety profile was in-line with that previously reported. Our results support that osimertinib plus savolitinib may overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-TKI. Further exploration of the osimertinib plus savolitinib combination is underway in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies.
Table
Part B: osimertinib 80 mg + savolitinib 600/300* mg
Part D: osimertinib 80 mg + savolitinib 300 mg
Endpoint
Previously treated with a 3G EGFR-TKI
No prior 3G EGFR-TKI, T790M-negative
No prior 3G EGFR-TKI, T790M-positive
No prior 3G EGFR-TKI, T790M-negative
n=69
n=51
n=18
n=42
ORR†, n (%)
[95% CI]
23 (33)
[22.4, 45.7]
33 (65)
[50.1, 77.6]
12 (67)
[41.0, 86.7]
26 (62)
[45.6, 76.4]
Median PFS, months
[95% CI]5.5
[4.1, 7.7]9.1
[5.5,12.8]11.1
[4.1,22.1]9.0
[5.6, 12.7]Total PFS events, n (%)
51 (74)
36 (71)
12 (67)
29 (69)
* Most patients were enrolled to 600 mg savolitinib, prior to weight-based dosing implementation, but following a protocol amendment, the final 21 patients enrolled in Part B were dosed with savolitinib by body weight as follows: patients who weighed ≤55 kg (n=7) received 300 mg daily and those weighing >55 kg (n=14) received 600 mg daily
†All confirmed responses were partial response.
3G, third generation; CI, confidence interval; ORR, objective response rate; PFS, progression-free survival
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
FP14.07 - Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions (ID 3402)
00:00 - 00:00 | Author(s): Helena Yu
- Abstract
- Presentation
Introduction
Selpercatinib is a highly selective and potent FDA-approved RET inhibitor that has demonstrated marked and durable efficacy in RET fusion-positive NSCLC. While RET fusions are the primary oncogenic driver in ~2% of NSCLC, RET fusions have also been identified as acquired resistance alterations following treatment with EGFR inhibitors, including osimertinib, in EGFR-mutant NSCLC. We sought to evaluate the safety and preliminary efficacy of the combination of osimertinib and selpercatinib in patients progressing on osimertinib.
Methods
Patients received selpercatinib in combination with osimertinib across three selpercatinib compassionate access programs: single patient protocols (SPP), named patient programs (NPPs), and an expanded access program (EAP). All patients had advanced EGFR-mutated NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected retrospectively.
Results
Across 12 patients identified, 11 had an EGFR exon 19 deletion (92%) and one had an EGFR L858R mutation (8%). The most common emergent RET fusion was CCDC6-RET (five patients, 42%), followed by NCOA4-RET (four patients, 33%), KIF5B-RET (two patients, 17%), and RUFY2-RET (one patient, 8%). All patients had received prior osimertinib and seven (58%) had also received a 1st or 2nd generation EGFR TKI. Most patients received selpercatinib at 80 mg BID (92%, range 100 mg QD - 120 mg BID) and osimertinib at 80 mg daily (75%, range 40 mg QD - 80 mg BID). Of twelve identified patients, 10 were evaluable for response per RECIST 1.1. Among RECIST evaluable patients five had a response (50%, four confirmed partial responses, one unconfirmed partial response). One patient, unevaluable per RECIST for non-measurable disease at baseline, demonstrated sustained clinical radiographic improvement ongoing at 8.2 months. The second unevaluable patient discontinued treatment prior to reassessment for unrelated clinical events preventing oral medication administration. The median duration of combination treatment across all 12 identified patients was 7.4 months (range 0.6 – 16.7+ months). For patients who achieved a RECIST response, the median treatment duration was 11 months (range 7.4 – 16.7+ months). Treatment was discontinued due to disease progression in seven patients, one patient discontinued for toxicity (grade 2 pneumonitis), one patient for intolerance to oral medication administration, and three patients remained on therapy at data cut-off. In one patient with a response lasting 10 months, plasma sequencing at resistance revealed persistence of EGFR 19del (22% AF) and RET fusion (0.4% AF) plus newly detected second-site resistance mutations in both EGFR (C797S, 0.1%) and RET (G810S, 0.8%), providing additional confirmation of the biologic relevance of the acquired RET fusion.
Conclusion
For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, with evidence of radiographic responses and durable benefit. These findings support future investigation of this combination, which will be evaluated prospectively as an arm of the phase 2 ORCHARD platform study (NCT03944772). The availability of active combination targeted therapy strategies highlights the need for assessment for genomic mechanisms of resistance following initial EGFR targeted therapy in NSCLC.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA03 - Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC (ID 100)
- Event: WCLC 2020
- Type: Oral
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
-
+
OA03.04 - Efficacy and Safety of the Novel HER3 Directed Antibody Drug Conjugate Patritumab Deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC (ID 3562)
10:30 - 11:30 | Presenting Author(s): Helena Yu
- Abstract
- Presentation
Introduction
There are few treatment options for patients with advanced EGFR-mutated (EGFRm) NSCLC after failure of EGFR TKIs and platinum-based chemotherapy. Here we report safety and activity in such patients treated in a phase 1 study (NCT03260491) with patritumab deruxtecan, a HER3 directed antibody drug conjugate, at the 5.6 mg/kg recommended dose for expansion. These data were previously presented at ESMO Congress 2020, Helena A. Yu et al., reused with permission.
Methods
The dose escalation part was presented previously. The dose expansion part enrolled patients with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy. Primary objective is assessment of activity by confirmed ORR (blinded independent central review, BICR); secondary objectives include evaluation of safety. Patritumab deruxtecan was administered IV Q3W.
Results
As of 30 April 2020, 57 patients from dose escalation and dose expansion were treated at the 5.6 mg/kg dose, and 56 patients were evaluable for response. Among 28 patients continuing treatment at data cut-off, 6 had only 1 tumor evaluation. Median prior anticancer regimens for metastatic disease was 4 (range, 1-9); 51 patients [90%] received prior platinum-based chemotherapy. Median number of prior EGFR TKIs was 2 (range, 1-4); 49 patients [86%] received prior osimertinib. 27 patients (47%) had history of central nervous system metastases. Median treatment duration was 3.5 months (range, 1-14 months); median follow up was 5.4 months (range, 0.3-15 months). The most common grade ≥3 treatment-emergent adverse events were platelet count decrease (25%) and neutrophil count decrease (16%). Efficacy for the 56 efficacy-evaluable patients is shown in the table below; 3 additional patients had partial response awaiting confirmation. HER3 was expressed in nearly all tumors. Efficacy was observed in patients with various mechanisms of EGFR TKI resistance, including EGFR C797S mutation, MET amplification, HER2 mutation, BRAF fusion, and PIK3CA mutation.
Conclusion
Patritumab deruxtecan at 5.6 mg/kg provides promising evidence of preliminary antitumor activity and safety in heavily pre-treated patients with locally advanced or metastatic EGFRm NSCLC.
Activity According to BICR Evaluation (Efficacy-Evaluable Population)
Dose escalation + dose expansion cohorts
EGFR mutated, 5.6 mg/kg patritumab deruxtecan
(N = 56)a
Confirmed BOR, n/N (%)
CR
1/56 (2)
PR
13/56 (23)
SD
25/56 (45)
PD
9/56 (16)
NE
8/56 (14)
Confirmed ORR, n/N (%)
95% CI
14/56 (25)
(14.4-38.4)
DCR, n/N (%)
95% CI
39/56 (70)
(55.9-81.2)
DoR (95% CI) in months, median (range)
7 (3.0-7.0)
a22/56 (39%) patients had best percentage decrease in sum of tumor diameters ≥ 30%.
BOR, best overall response; ORR, objective response rate; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P01.01 - HERTHENA-Lung01: A Randomized Phase 2 Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Previously Treated Metastatic EGFR-mutated NSCLC (ID 3412)
00:00 - 00:00 | Author(s): Helena Yu
- Abstract
Introduction
Few treatment options have demonstrated meaningful therapeutic benefit for patients with epidermal growth factor receptor- (EGFR-) mutated non-small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in the majority of EGFR-mutated NSCLC, and expression has been associated with worse clinical outcomes. Currently, there are no approved HER3 directed therapies for the treatment of NSCLC. Patritumab deruxtecan is a novel, investigational antibody drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In an ongoing Phase 1 study of patritumab deruxtecan in patients with EGFR-mutated TKI-resistant NSCLC, preliminary evidence of safety and antitumor activity were observed, providing proof of concept of patritumab deruxtecan. This Phase 2 study (HERTHENA-Lung01) is further evaluating patritumab deruxtecan in patients with previously treated metastatic or locally advanced EGFR-mutated NSCLC.
Methods
This is a randomized, open-label, global Phase 2 study that will enroll up to 300 patients at approximately 60 study sites across North America, Europe, and Asia. Eligible patients will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and at least 1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Patients with an EGFR T790M mutation must have received and progressed on prior osimertinib. Patients will be excluded if they have evidence of previous small cell or combined small cell/non-small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. The HER3 expression results will not be used to select patients for enrollment. Two Q3W dose regimens will be independently evaluated: 5.6 mg/kg patritumab deruxtecan in a fixed-dose regimen (Arm 1), or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg). Patients will be randomized 1:1 to receive 1 of the 2 regimens. After initial review of ongoing phase 1 study data in an interim analysis, a decision will be made to continue with enrollment into 1 or both study arms. The primary objective of the study is to evaluate the efficacy of patritumab deruxtecan as measured by objective response rate (ORR) according to BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of patritumab deruxtecan, as well as to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator assessment per RECIST v1.1, disease control rate, time to response, best percentage change in the sum of diameters of measurable lesions, and overall survival. Anticipated total study duration is expected to be 26 months, consisting of approximately 12 months for enrollment and 14 months on treatment. The study is planned to begin in 2020.
-
+
P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P76.27 - ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib (ID 1397)
00:00 - 00:00 | Author(s): Helena Yu
- Abstract
Introduction
Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647).
Methods
In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented.
