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Jhanelle Elaine Gray
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FP13 - Immunotherapy (Phase II/III Trials) (ID 247)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP13.02 - Pembrolizumab + Pemetrexed-Platinum vs Pemetrexed-Platinum for Metastatic NSCLC: 4-Year Follow-up From KEYNOTE-189 (ID 3194)
00:00 - 00:00 | Presenting Author(s): Jhanelle Elaine Gray
- Abstract
- Presentation
Introduction
In the randomized, double-blind, phase 3 KEYNOTE-189 trial (NCT02578680) pembrolizumab plus pemetrexed-platinum chemotherapy significantly improved OS and PFS vs placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 expression. We present efficacy and safety outcomes after ~4 years of follow-up.
Methods
Patients were randomized (2:1) to intravenous pembrolizumab 200 mg or placebo Q3W for up to 35 cycles (2 years). All patients received pemetrexed and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pemetrexed. Treatment continued until radiographic progression/unacceptable toxicity. Crossover from placebo plus chemotherapy to pembrolizumab monotherapy was permitted after PD. Patients who experienced SD or better during initial treatment or crossover phases with pembrolizumab and then experienced PD at any time during the follow-up period could receive second-course pembrolizumab (17 cycles). The primary endpoints were OS and PFS.
Results
616 patients were randomized (pembrolizumab plus pemetrexed-platinum, n=410; placebo plus pemetrexed-platinum, n=206). Median (range) time from randomization to data cutoff (August 28, 2020) was 46.3 (41.8–54.1) months. 84 patients (40.8%) randomized to the control group crossed over to pembrolizumab monotherapy on-study. Efficacy outcomes are summarized in the Table. Median (95% CI) OS was 22.0 (19.5‒24.5) months with pembrolizumab plus pemetrexed-platinum vs 10.6 (8.7‒13.6) months with placebo plus pemetrexed-platinum (hazard ratio [HR], 0.60; 95% CI, 0.50‒0.72). 3-year OS rate was 31.3% vs 17.4%. Median (95% CI) PFS was 9.0 (8.1‒10.4) months vs 4.9 (4.7‒5.5) months, respectively (HR, 0.50; 95% CI, 0.41‒0.59). Grade 3‒5 AEs occurred in 72.1% patients in the pembrolizumab plus pemetrexed-platinum group and 67.3% patients in the placebo plus pemetrexed-platinum group. Among 56 patients who completed 35 cycles (2 years) of pembrolizumab, 49 (87.5%) had an objective response (CR, n=6; PR, n=43) and 7 (12.5%) had SD. 45 patients (80.4%) were alive at data cutoff (28 without PD), and 2-year OS after completion of 35 cycles was 79.6%. At data cutoff, 7 patients had initiated second-course pembrolizumab.
ConclusionTable. Efficacy Outcomes in the ITT Population and in Subgroups Defined by PD-L1 TPSa
ITT
N=616TPS ≥50%
n=202TPS 1%-49%
n=186TPS <1%
n=190OS HR (95% CI)b
0.60 (0.50–0.72)
0.71 (0.50–1.00)
0.66 (0.47–0.93)
0.52 (0.37–0.72)
3-yr OS rate,b %
31.3 vs 17.4
43.7 vs 30.0
28.3 vs 17.2
23.3 vs 5.3
PFS HR (95% CI)b,c
0.50 (0.41–0.59)
0.36 (0.26–0.49)
0.54 (0.39–0.76)
0.68 (0.49–0.93)
PFS2 HR (95% CI)b,c,d
0.52 (0.43–0.63)
0.55 (0.39–0.77)
0.59 (0.42–0.83)
0.49 (0.35–0.68)
ORR,c %
48.3 vs 19.9
62.1 vs 25.7
50.0 vs 20.7
33.1 vs 14.3
Median DOR,b,c mo
12.6 vs 7.1
15.1 vs 7.1
13.6 vs 7.6
10.8 vs 7.8
DOR, duration of response; ITT, intention-to-treat; TPS, tumor proportion score
aAll outcomes are pembrolizumab plus pemetrexed-platinum vs placebo plus pemetrexed-platinum.
bKaplan-Meier estimate.
cPer RECIST version 1.1 by blinded independent central review.
dPFS2 was defined as the time from randomization to second/subsequent tumor progression on next-line treatment/death (per investigator assessment per RECIST version 1.1).
With ~4 years of follow-up, pembrolizumab plus pemetrexed-platinum continued to provide OS and PFS benefit vs pemetrexed-platinum alone in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, irrespective of PD-L1 expression. Patients who received 35 cycles of pembrolizumab had durable responses and most were alive at data cutoff. Toxicity was manageable. Pembrolizumab plus pemetrexed-platinum remains a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC.
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MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA13.07 - Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity (ID 3760)
16:45 - 17:45 | Author(s): Jhanelle Elaine Gray
- Abstract
Introduction
While osimertinib has resulted in striking improvements in outcomes for patients with NSCLC harboring classical EGFR mutations (Ex19del, L858R, and/or T790M), patients with atypical EGFR mutations have shown heterogeneous and in some cases inferior responses to EGFR inhibitors. The frequency, structural and clinical implications of atypical EGFR mutations are less understood.
Methods
We characterized the mutational landscape (N=16,715 patients with EGFR mutations), in vitro sensitivity (N=70 Ba/F3 cell lines), and in silico structure of primary and co-occurring acquired EGFR mutations to determine functional groups. Clinical outcomes in patients with atypical EGFR mutations treated with EGFR TKIs were evaluated through a retrospective analysis from the MD Anderson GEMINI database and Moffitt Cancer Center.
Results
Among EGFR mutant NSCLC patients, 67% had classical mutations, 31% had atypical EGFR mutations, and 3% had a tertiary mutation including Ex19del/L858R with T790M plus an atypical mutation. Atypical mutations included exon 20 insertions (9%), other primary atypical mutations (13%), and complex mutations including an atypical mutation (9%). EGFR mutations could be separated into four distinct functional subgroups: 1) classical-like, 2) T790M-like including a subset of tertiary mutations, 3) exon 20 insertions, and 4) ATP-Binding Pocket Volume-Reducing (PVR) mutations. The classical-like were broadly sensitive to 1st, 2nd, and 3rd-generation inhibitors with a drug binding pocket similar to classical mutations. T790M-like mutations were sensitive to 3rd-generation EGFR inhibitors, but resistant to first- and second-generation inhibitors irrespective of co-occurring mutations. Tertiary mutations were generally resistant to EGFR inhibitors, but a drug repurposing screen identified select PKC and ALK inhibitors as having activity. The exon 20 insertion mutations, which cause significant reduction in drug binding pocket volume, were highly resistant to the majority of EGFR inhibitors but sensitive to novel exon 20 specific inhibitors. Lastly, we found a fourth group of mutations, ATP-Binding Pocket Volume Reducing (PVR) mutations that were associated with resistance to 1st- and 3rd-generation inhibitors, but selectively sensitive to quinazoline-based, 2nd-generation inhibitors such as afatinib and poziotinib preclinically. These mutations were primary located in the P-loop (exon 18), the c-terminal loop of the αc-helix (exon 20), and the A-loop (exon 21) of EGFR. Retrospective analysis of patients with PVR mutations revealed that patients had a significantly longer median progression free survival (mPFS) when treated with a 2nd-generation inhibitor (mPFS = 24mo) versus a 1st-generation (mPFS = 9.5mo, p = 0.013, HR = 4.2) or 3rd-generation inhibitor (mPFS = 6.4mo, p <0.0001, HR = 3.4). Three patients with NSCLC, who acquired PVR mutations after first-line osimertinib treatment had clinical benefit after receiving 2nd-generation EGFR inhibitors.
Conclusion
EGFR mutations can be separated into four distinct subgroups based on the structural changes caused by the mutation and differential sensitivity to EGFR inhibitors. The PVR subgroup, largely comprised of exon 18 or 20 point mutations, had greater relative sensitivity to 2nd-generation drugs with a quinazoline core than 3rd-generation drugs such as osimertinib in vitro, and improved outcomes in patients treated with these agents compared with osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.
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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
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OA03.01 - Chair (ID 4221)
10:30 - 11:30 | Presenting Author(s): Jhanelle Elaine Gray
- Abstract
Abstract not provided
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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
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P76.62 - RAMOSE: An Open-Label Randomized Phase II Study of Osimertinib with or without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 3246)
00:00 - 00:00 | Author(s): Jhanelle Elaine Gray
- Abstract
Introduction
The third-generation EGFR tyrosine kinase inhibitor osimertinib is currently used as a standard first-line therapy for patients with metastatic EGFR-mutant NSCLC. However, a majority of patients’ cancers will develop resistance to osimertinib in less than 2 years, with a median progression-free survival of approximately 19 months.
Preclinical models demonstrate upregulated VEGF signaling as a mechanism of acquired resistance to EGFR therapies, and improved efficacy when combining VEGF and EGFR inhibition. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, was recently approved by the US FDA in combination with erlotinib in patients with metastatic untreated EGFR-mutant NSCLC, based on a significant improvement in progression-free survival (PFS) with the combination seen in the RELAY trial.
A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With this strong preclinical and clinical evidence, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.
Methods
RAMOSE (HCRN LUN-18-335; NCT03909334) is a randomized, open-label phase 2 study comparing osimertinib 80mg PO daily + ramucirumab 10 mg/kg IV q3 weeks (O + R) to osimertinib 80mg PO daily monotherapy (O) for initial treatment of metastatic EGFR-mutant NSCLC. Patients are randomized 2:1 to the O+R versus O groups, with stratification based on type of EGFR mutation and presence of CNS metastasis. The trial plans to enroll total of 150 patients, allocating 100 to O+R and 50 to O monotherapy. The primary endpoint is PFS. Secondary endpoints include ORR, OS and DCR, as well as safety/toxicity. Major inclusion criteria include patients with metastatic NSCLC harboring activating EGFR mutations (L858R or Exon 19 del). Major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. We hypothesize an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65.
The study is currently open at 9 sites in the USA, with additional sites planned. Hoosier Cancer Research Network is facilitating execution of the trial. Analysis by a study Data Safety Monitoring Board (DSMB) is performed annually. In addition, a planned interim analysis for efficacy will be performed after the first 75 subjects are enrolled.
Results
The trial opened to accrual in July 2019. As of July 02, 2020 (the data cutoff for planned DSMB analysis), 29 patients had been accrued. 25 of these patients were randomized (17 to O+R arm and 8 to O arm). Among the patients currently evaluable for toxicity (N=19), grade 3 or higher adverse events (AEs) were reported in 5/14 patients on O+R arm, versus 1/5 patients on O arm. In the O+R arm, grade 3 AEs included hypertension (n=1), pleural catheter infection (n=1), musculoskeletal pain (n=1), neutrophil count decreased (n=1), and dyspnea (n=1).
Conclusion
Early analysis from the RAMOSE trial shows no unexpected signals of toxicity with the combination of O+R. Enrollment for the trial is ongoing.
